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1.  Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cells 
PLoS Medicine  2008;5(5):e100.
Virus-specific CD8+ T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8+ T cells with a “polyfunctional” profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8+ T cell responses on the single-epitope level over time, starting in primary HIV-1 infection.
Methods and Findings
We longitudinally analyzed the polyfunctional epitope-specific CD8+ T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8+ T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8+ T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%–72%) to 76% (56%–95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%–75%) to 56% (42%–70%) (SD of the effect size 0.18) (p < 0.05).
These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.
Marcus Altfeld and colleagues suggest that the exhaustion of virus-specific CD8+ T cells during chronic HIV infection likely results from the persistence of antigen.
Editors' Summary
Viruses are small infectious agents responsible for many human diseases, including acquired immunodeficiency syndrome (AIDS). Like other viruses, the human immunodeficiency virus 1 (HIV-1; the cause of AIDS) enters human cells and uses the cellular machinery to replicate before bursting out of its temporary home. During the initial stage of HIV infection, a particular group of cells in the human immune system, CD8+ T cells, are thought to be important in controlling the level of the virus. These immune system cells recognize pieces of viral protein called antigens displayed on the surface of infected cells; different subsets of CD8+ T cells recognize different antigens. When a CD8+ T cell recognizes its specific antigen (or more accurately, a small part of the antigen called an “epitope”), it releases cytotoxins (which kill the infected cells) and cytokines, proteins that stimulate CD8+ T cell proliferation and activate other parts of the immune system. With many viruses, when a person first becomes infected (an acute viral infection), antigen-specific CD8+ T cells completely clear the infection. But with HIV-1 and some other viruses, these cells do not manage to remove all the viruses from the body and a chronic (long-term) infection develops, during which the immune system is constantly exposed to viral antigen.
Why Was This Study Done?
In HIV-1 infections (and other chronic viral infections), virus-specific CD8+ T cells lose their ability to proliferate, to make cytokines, and to kill infected cells as patients progress to the long-term stages of infection. That is, the virus-specific CD8+ T cells gradually lose their “effector” functions and become functionally impaired or “exhausted.” “Polyfunctional” CD8+ T cells (those that release multiple cytokines in response to antigen) are believed to be essential for an effective CD8+ T cell response, so scientists trying to develop HIV-1 vaccines would like to stimulate the production of this type of cell. To do this they need to understand why these polyfunctional cells are lost during chronic infections. Is their loss the cause or the result of viral persistence? In other words, does the constant presence of viral antigen lead to the exhaustion of CD8+ T cells during chronic HIV infection? In this study, the researchers investigate this question by looking at the polyfunctionality of CD8+ cells responding to several different viral epitopes at various times during HIV-1 infection, starting very early after infection with HIV-1 had occurred.
What Did the Researchers Do and Find?
The researchers enrolled 18 patients recently infected with HIV-1 and analyzed their CD8+ T cell responses to specific epitopes at various times after enrollment using a technique called flow cytometry. They found that the epitope-specific CD8+ cells produced several effector proteins after antigen stimulation during the initial stage of HIV-1 infection, but lost their polyfunctionality in the face of persistent viral infection. The CD8+ T cells also increased their production of programmed death 1 (PD-1), a protein that has been shown to be associated with the functional impairment of CD8+ T cells. Some of the patients began antiretroviral therapy during the study, and the researchers found that this treatment, which reduced the viral load, reversed CD8+ T cell exhaustion. Finally, the appearance in the patients' blood of viruses that had made changes in the specific epitopes recognized by the CD8+ T cells to avoid being killed by these cells, also reversed the exhaustion of the T cells recognizing these particular epitopes.
What Do These Findings Mean?
These findings suggest that the constant presence of HIV-1 antigen causes the functional impairment of virus-specific CD8+ T cell responses during chronic HIV-1 infections. Treatment with antiretroviral drugs reversed this functional impairment by reducing the amount of antigen in the patients. Similarly, the appearance of viruses with altered epitopes, which effectively reduced the amount of antigen recognized by those epitope-specific CD8+ T cells without reducing the viral load, also reversed T cell exhaustion. These results would not have been seen if the functional impairment of CD8+ cells were the cause rather than the result of antigen persistence. By providing new insights into how the T cell response to viruses evolves during persistent viral infections, these findings should help in the design of vaccines against HIV and other viruses that cause chronic viral infections.
Additional Information.
Please access these Web sites via the online version of this summary at
Read a related PLoS Medicine Research in Translation article
Learn more from the researchers' Web site, the Partners AIDS Research Center
Wikipedia has a page on cytotoxic T cells (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a detailed article on the immunopathogenesis of HIV infection
NAM, a UK registered charity, provides information about all aspects of HIV and AIDS, including a fact sheet on the stages of HIV infection and on the immune response to HIV
Information is available from Avert, an international AIDS charity, on all aspects of HIV/AIDS, including information on the stages of HIV infection
PMCID: PMC2365971  PMID: 18462013
2.  Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study 
PLoS Medicine  2013;10(10):e1001542.
Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
Methods and Findings
CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization–recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa.
Why Was This Study Done?
World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation.
What Did the Researchers Do and Find?
To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study.
What Do These Findings Mean?
These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa and on HIV infection in children (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the UNAIDS's 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children can be downloaded
Information about the ARROW trial is available
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
PMCID: PMC3812080  PMID: 24204216
3.  Host HLA B*Allele-Associated Multi-Clade Gag T-Cell Recognition Correlates with Slow HIV-1 Disease Progression in Antiretroviral Therapy-Naïve Ugandans 
PLoS ONE  2009;4(1):e4188.
Some HIV infected individuals remain asymptomatic for protracted periods of time in the absence of antiretroviral therapy (ART). Virological control, CD4 T cell loss and HIV-specific responses are some of the key interrelated determinants of HIV-1 disease progression. In this study, possible interactions between viral load, CD4 T cell slopes, host genetics and HIV-specific IFN-γ responses were evaluated in chronically HIV-1-infected adults.
Methodolology/Principal Findings
Multilevel regression modeling was used to stratify clade A or D HIV-infected individuals into disease progression groups based on CD4 T cell slopes. ELISpot assays were used to quantify the frequency and magnitude of HIV-induced IFN-γ responses in 7 defined rapid progressors (RPs) and 14 defined slow progressors (SPs) at a single time point. HLA typing was performed using reference strand conformational analysis (RSCA). Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-γ response correlated with viral load, slow disease progression was associated with over-representation of host immunogenetic protective HLA B* alleles (10 of 14 SPs compared to 0 of 7; p = 0.004, Fisher's Exact) especially B*57 and B*5801, multiclade Gag T-cell targeting (71%, 10 of 14 SPs compared to 14%, 1 of 7 RPs); p = 0.029, Fisher's Exact test and evident virological control (3.65 compared to 5.46 log10 copies/mL in SPs and RPs respectively); p<0.001, unpaired student's t-test
These data are consistent with others that associated protection from HIV disease with inherent host HLA B allele-mediated ability to induce broader Gag T-cell targeting coupled with apparent virological control. These immunogenetic features of Gag-specific immune response which could influence disease progression may provide useful insight in future HIV vaccine design.
PMCID: PMC2617765  PMID: 19142234
4.  Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease 
Retrovirology  2006;3:73.
The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1–V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants.
Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1–V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression.
Our data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.
PMCID: PMC1635063  PMID: 17054795
5.  Factors associated with conversion of long-term non-progressors to progressors: A prospective study of HIV perinatally infected paediatric survivors 
Background & objectives:
Survival pattern among children infected with the human immune deficiency virus (HIV) follows a bimodel distribution. Some children survive beyond 9 years age and are known as long term survivers (LTS) while others had a more rapid course to death during the first few years of life. In the LTS group of children, two sub-populations have emerged, the long term non-progressors (LTNP) who have remained asymptomatic over a period of years and those who have survived despite clinical and laboratory evidence of disease progression, the long term progressors (LTP). The aim of the present study was to determine the factors influencing the conversion of LTNPs to LTPs in a group of perinatally HIV infected children who were followed up for five years.
A total of 26 HIV seropositive paediatric patients were monitored from 2006 to 2011 with CD4 cell counts, onset of clinical manifestations, body weight, biochemical, haematological and immunological parameters. Statistical analyses, both qualitative and quantitative, were used to determine the degree of conversion of non-progressors to progressors.
All 26 (13 female and 13 male) perinatally HIV infected children, born during1991-1996 were healthy until 2006. But by 2011, 18 were placed in progressors group with antiretroviral therapy (ART), while six remained in non progressors group and two died. As per the Kaplan-Meier survival analysis, AIDS free median survival period (years) in LTP group (CD4 count) of the cohort was 10±0.66 (<200; P=<0.05); 11±0.61 (200-350, P=<0.05), 12±0.18 (>350, P=<0.05). Intercurrent and opportunistic infections (OIs) were observed in LTPs only. The incidence of OI in LTPs was higher when compared to general paediatric population.
Interpretation & conclusions:
Our findings show that CD4 counts and OIs play an important role in influencing the survival chances of perinatally HIV infected children.
PMCID: PMC3818594  PMID: 24135176
AIDS; HIV; LTNPs; LTP; paediatric; progressors
6.  Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection 
PLoS ONE  2015;10(6):e0128714.
Understanding the factors that delineate the efficacy of T cell responses towards pathogens is crucial for our ability to develop potent therapies against infectious diseases. Multidimensional evaluation of T cell functionality at the single-cell level enables exhaustive analysis of combinatorial functional properties, hence polyfunctionality. We have recently invented an algorithm that quantifies polyfunctionality, the Polyfunctionality Index (Larsen et al. PLoS One 2012). Here we demonstrate that quantitative assessment of T cell polyfunctionality correlates with T cell efficacy measured as the capacity to kill target cells in vitro and control infection in vivo.
We employed the polyfunctionality index on two datasets selected for their unique ability to evaluate the polyfunctional imprint on T cell efficacy. 1) HIV-specific CD8+ T cells and 2) Leishmania major-specific CD4+ T cells were analysed for their capacity to secrete multiple effector molecules, kill target cells and control infection. Briefly, employing the Polyfunctionality Index algorithm we determined the parameter estimates resulting in optimal correlation between T cell polyfunctionality and T cell efficacy.
T cell polyfunctionality is correlated with T cell efficacy measured as 1) target killing (r=0.807, P<0.0001) and 2) lesion size upon challenge with Leishmania major (r=-0.50, P=0.004). Contrary to an approach relying on the Polyfunctionality Index algorithm, quantitative evaluation of T cell polyfunctionality traditionally ignores the gradual contribution of more or less polyfunctional T cells. Indeed, comparing both approaches we show that optimal description of T cell efficacy is obtained when gradually integrating all levels of polyfunctionality in accordance with the Polyfunctionality Index.
Our study presents a generalizable methodology to objectively evaluate the impact of polyfunctionality on T cell efficacy. We show that T cell polyfunctionality is a superior correlate of T cell efficacy both in vitro and in vivo as compared with response size. Therefore, future immunotherapies should aim to increase T cell polyfunctionality.
PMCID: PMC4457486  PMID: 26046523
7.  Nef-specific CD45RA+ CD8+ T cells secreting MIP-1β but not IFN-γ are associated with nonprogressive HIV-1 infection 
Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.
We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.
The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.
PMCID: PMC2909146  PMID: 20598119
8.  Human Immunodeficiency Virus (HIV)-Specific Gamma Interferon Secretion Directed against All Expressed HIV Genes: Relationship to Rate of CD4 Decline 
Journal of Virology  2005;79(8):4908-4917.
Immune responses to human immunodeficiency virus (HIV) are detected at all stages of infection and are believed to be responsible for controlling viremia. This study seeks to determine whether gamma interferon (IFN-γ)-secreting HIV-specific T-cell responses influence disease progression as defined by the rate of CD4 decline. The study population consisted of 31 subjects naïve to antiretroviral therapy. All were monitored clinically for a median of 24 months after the time they were tested for HIV-specific responses. The rate of CD4+-T-cell loss was calculated for all participants from monthly CD4 counts. Within this population, 17 subjects were classified as typical progressors, 6 subjects were classified as fast progressors, and 8 subjects were classified as slow progressors. Peripheral blood mononuclear cells were screened for HIV-specific IFN-γ responses to all expressed HIV genes. Among the detected immune responses, 48% of the recognized peptides were encoded by Gag and 19% were encoded by Nef gene products. Neither the breadth nor the magnitude of HIV-specific responses correlated with the viral load or rate of CD4 decline. The breadth and magnitude of HIV-specific responses did not differ significantly among typical, fast, and slow progressors. These results support the conclusion that although diverse HIV-specific IFN-γ-secreting responses are mounted during the asymptomatic phase, these responses do not seem to modulate disease progression rates.
PMCID: PMC1069552  PMID: 15795276
9.  CRF01_AE-Specific Neutralizing Activity Observed in Plasma Derived from HIV-1-Infected Thai Patients Residing in Northern Thailand: Comparison of Neutralizing Breadth and Potency between Plasma Derived from Rapid and Slow Progressors 
PLoS ONE  2013;8(1):e53920.
Development of a protective vaccine against human immunodeficiency virus type 1 (HIV-1) is an important subject in the field of medical sciences; however, it has not yet been achieved. Potent and broadly neutralizing antibodies are found in the plasma of some HIV-1-infected patients, whereas such antibody responses have failed to be induced by currently used vaccine antigens. In order to develop effective vaccine antigens, it is important to reveal the molecular mechanism of how strong humoral immune responses are induced in infected patients. As part of such studies, we examined the correlation between the anti-HIV-1 neutralizing antibody response and disease progression.
Methodology/Principal Findings
We evaluated the anti-HIV-1 neutralizing activity of plasma derived from 33 rapid and 34 slow progressors residing in northern Thailand. The level of neutralizing activity varied considerably among plasmas, and no statistically significant differences in the potency and breadth of neutralizing activities were observed overall between plasma derived from rapid and slow progressors; however, plasma of 4 slow progressors showed neutralizing activity against all target viruses, whereas none of the plasma of rapid progressors showed such neutralizing activity. In addition, 21% and 9% of plasmas derived from slow and rapid progressors inhibited the replication of more than 80% of CRF01_AE Env-recombinant viruses tested, respectively. Neutralization of subtype B and C Env-recombinant viruses by the selected plasma was also examined; however, these plasma samples inhibited the replication of only a few viruses tested.
Although no statistically significant differences were observed in the potency and breadth of anti-HIV-1 neutralizing activities between plasma derived from rapid and slow progressors, several plasma samples derived from slow progressors neutralized CRF01_AE Env-recombinant viruses more frequently than those from rapid progressors. In addition, plasma derived from HIV-1-infected Thai patients showed CRF01_AE-specific neutralizing activity.
PMCID: PMC3538751  PMID: 23308290
10.  Perforin Expression Directly Ex Vivo by HIV-Specific CD8+ T-Cells Is a Correlate of HIV Elite Control 
PLoS Pathogens  2010;6(5):e1000917.
Many immune correlates of CD8+ T-cell-mediated control of HIV replication, including polyfunctionality, proliferative ability, and inhibitory receptor expression, have been discovered. However, no functional correlates using ex vivo cells have been identified with the known ability to cause the direct elimination of HIV-infected cells. We have recently discovered the ability of human CD8+ T-cells to rapidly upregulate perforin—an essential molecule for cell-mediated cytotoxicity—following antigen-specific stimulation. Here, we examined perforin expression capability in a large cross-sectional cohort of chronically HIV-infected individuals with varying levels of viral load: elite controllers (n = 35), viremic controllers (n = 29), chronic progressors (n = 27), and viremic nonprogressors (n = 6). Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin upregulation, cytokine production, and degranulation following stimulation with overlapping peptide pools encompassing all proteins of HIV. We observed that HIV-specific CD8+ T-cells from elite controllers consistently display an enhanced ability to express perforin directly ex vivo compared to all other groups. This ability is not restricted to protective HLA-B haplotypes, does not require proliferation or the addition of exogenous factors, is not restored by HAART, and primarily originates from effector CD8+ T-cells with otherwise limited functional capability. Notably, we found an inverse relationship between HIV-specific perforin expression and viral load. Thus, the capability of HIV-specific CD8+ T-cells to rapidly express perforin defines a novel correlate of control in HIV infection.
Author Summary
While the majority HIV-infected individuals progress to AIDS, a fraction of these individuals—for reasons not completely understood—do not develop AIDS and also display sustained control over viral replication; these subjects are sometimes referred to as elite controllers (EC). Prior evidence has shown that HIV-specific CD8+ T-cells, a component of adaptive immunity against intracellular pathogens, from EC exhibit enhanced functionality compared to individuals with progressive disease. Therefore, HIV-specific CD8+ T-cells likely play an important role in the favorable clinical outcomes witnessed in EC. We show in this study that the ability to control HIV replication in EC is associated with the expression of a protein called perforin, a critical molecule that enables CD8+ T-cells to directly kill infected cells - thereby preventing the spread of HIV to previously uninfected cells. In infected subjects with nonprogressive disease, we show that HIV-specific CD8+ T-cells demonstrate a superior ability to express perforin upon antigen-specific stimulation, whereas in progressors this property is diminished. Thus, we identify a functional capability of CD8+ T-cells, readily measured by standard intracellular cytokine staining assays, that potentially has a direct impact on HIV replication in vivo. These findings may, therefore, provide an important qualifier for future HIV vaccine research.
PMCID: PMC2877741  PMID: 20523897
11.  Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection▿  
Journal of Virology  2009;83(19):10234-10244.
A broad Gag-specific CD8+ T-cell response is associated with effective control of adult human immunodeficiency virus (HIV) infection. The association of certain HLA class I molecules, such as HLA-B*57, -B*5801, and -B*8101, with immune control is linked to mutations within Gag epitopes presented by these alleles that allow HIV to evade the immune response but that also reduce viral replicative capacity. Transmission of such viruses containing mutations within Gag epitopes results in lower viral loads in adult recipients. In this study of pediatric infection, we tested the hypothesis that children may tend to progress relatively slowly if either they themselves possess one of the protective HLA-B alleles or the mother possesses one of these alleles, thereby transmitting a low-fitness virus to the child. We analyzed HLA type, CD8+ T-cell responses, and viral sequence changes for 61 mother-child pairs from Durban, South Africa, who were monitored from birth. Slow progression was significantly associated with the mother or child possessing one of the protective HLA-B alleles, and more significantly so when the protective allele was not shared by mother and child (P = 0.007). Slow progressors tended to make CD8+ T-cell responses to Gag epitopes presented by the protective HLA-B alleles, in contrast to progressors expressing the same alleles (P = 0.07; Fisher's exact test). Mothers expressing the protective alleles were significantly more likely to transmit escape variants within the Gag epitopes presented by those alleles than mothers not expressing those alleles (75% versus 21%; P = 0.001). Reversion of transmitted escape mutations was observed in all slow-progressing children whose mothers possessed protective HLA-B alleles. These data show that HLA class I alleles influence disease progression in pediatric as well as adult infection, both as a result of the CD8+ T-cell responses generated in the child and through the transmission of low-fitness viruses by the mother.
PMCID: PMC2748050  PMID: 19605475
12.  Evolution of human immunodeficiency virus type 1 env sequence variation in patients with diverse rates of disease progression and T-cell function. 
Journal of Virology  1997;71(3):1871-1879.
We examined the relationship between env sequence variation and disease progression in 10 human immunodeficiency virus type 1 (HIV-1)-seropositive subjects selected from a longitudinal cohort receiving zidovudine therapy. Five subjects were chosen for stable clinical status and CD4 counts (slow progressors), and five were selected for rapid clinical deterioration and CD4 count decline (rapid progressors). The slow progressors had significantly lower plasma viral RNA loads and greater lymphoproliferative responses to mitogens than the rapid progressors. DNA sequences representing the C1 through C3 regions of env were amplified from two peripheral blood mononuclear cell DNA samples from each subject separated by an average of 2.5 years. Molecular clones of these amplicons were then sequenced, and DNA sequence and deduced amino acid sequence distances were compared. Inter-time point sequence comparison showed a higher rate of sequence evolution for the rapid progressors in three of five matched pairs of rapid progressors and slow progressors and for the slow progressors in the remaining two subject pairs. However, intra-time point sequence comparisons showed that four of five slow progressors developed a more diverse quasispecies over time and one showed no change. In contrast, four of five rapid progressors showed no change in quasispecies diversity over time and one showed a significant decrease in diversity. The overall C1 through C3 region quasispecies diversity in the slow progressors at baseline was lower than that for the rapid progressors, but this difference was not significant at the follow-up time points. These diversity relationships were obscured if sequence analyses were limited to the 300-bp C2 to V3 region. Thus, HIV-1 quasispecies diversity increased over time in subjects with more functional immune systems.
PMCID: PMC191257  PMID: 9032317
13.  Receptor-Ligand Requirements for Increased NK Cell Polyfunctional Potential in Slow Progressors Infected with HIV-1 Coexpressing KIR3DL1*h/*y and HLA-B*57▿† 
Journal of Virology  2011;85(12):5949-5960.
Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor–HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.
PMCID: PMC3126301  PMID: 21471235
14.  Immunity to HIV in Early Life 
The developing immune system is adapted to the exposure to a plethora of pathogenic and non-pathogenic antigens encountered in utero and after birth, requiring a fine balance between protective immunity and immune tolerance. In early stages of life, this tolerogenic state of the innate and adaptive immune system and the lack of immunological memory render the host more susceptible to infectious pathogens like HIV. HIV pathogenesis is different in children, compared to adults, with more rapid disease progression and a substantial lack of control of viremia compared to adults. Plasma viral load remains high during infancy and only declines gradually over several years in line with immune maturation, even in rare cases where children maintain normal CD4 T-lymphocyte counts for several years without antiretroviral therapy (ART). These pediatric slow progressors also typically show low levels of immune activation despite persistently high viremia, resembling the phenotype of natural hosts of SIV infection. The lack of immunological memory places the fetus and the newborn at higher risk of infections; however, it may also provide an opportunity for unique interventions. Frequencies of central memory CD4+ T-lymphocytes, one of the main cellular reservoirs of HIV, are very low in the newborn child, so immediate ART could prevent the establishment of persistent viral reservoirs and result in “functional cure.” However, as recently demonstrated in the case report of the “Mississippi child” who experienced viral rebound after more than 2 years off ART, additional immunomodulatory strategies might be required for sustained viral suppression after ART cessation. In this review, we discuss the interactions between HIV and the developing immune system in children and the potential implications for therapeutic and prophylactic interventions.
PMCID: PMC4130105  PMID: 25161656
HIV; pediatric; innate immunity; adaptive immunity; immune responses; immune activation; immune exhaustion; viral reservoir
15.  Evolution of human immunodeficiency virus type 1 in perinatally infected infants with rapid and slow progression to disease. 
Journal of Virology  1997;71(6):4694-4706.
We addressed the relationship between the origin and evolution of human immunodeficiency virus type 1 (HIV-1) variants and disease outcome in perinatally infected infants by studying the V3 regions of viral variants in samples obtained from five transmitting mothers at delivery and obtained sequentially over the first year of life from their infected infants, two of whom (rapid progressors) rapidly progressed to having AIDS. Phylogenetic analyses disclosed that the V3 sequences from each mother-infant pair clustered together and were clearly distinct from those of the other pairs. Within each pair, the child's sequences formed a monophyletic group, indicating that a single variant initiated the infection in both rapid and slow progressors. Plasma HIV-1 RNA levels increased in all five infants during their first months of life and then declined within the first semester of life only in the three slow progressors. V3 variability increased over time in all infants, but no differences in the pattern of V3 evolution in terms of potential viral phenotype were observed. The numbers of synonymous and nonsynonymous substitutions varied during the first semester of life regardless of viral load, CD4+-cell count, and disease progression. Conversely, during the second semester of life the rate of nonsynonymous substitutions was higher than that of synonymous substitutions in the slow progressors but not in the rapid progressors, thus suggesting a stronger host selective pressure in the former. In view of the proposal that V3 genetic evolution is driven mainly by host immune constraints, these findings suggest that while the immune response to V3 might contribute to regulating viral levels after the first semester of life, it is unlikely to play a determinant role in the initial viral decline soon after birth.
PMCID: PMC191691  PMID: 9151863
16.  Increased memory differentiation is associated with decreased polyfunctionality for HIV but not for CMV-specific CD8+ T cells 
The generation of polyfunctional CD8+ T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8+ T cells within different memory subpopulations in 20 ART-naïve HIV-1 infected individuals at approximately 34 weeks post infection. These profiles were compared with CMV-specific CD8+ T cell responses in HIV-uninfected controls and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8+ T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO+CD27+) exhibited a higher proportion of cells positive for three or four functions (p<0.001), and a lower proportion of mono-functional cells (p<0.001) compared to terminally-differentiated (CD45RO−CD27−) HIV-specific CD8+ T cells. The majority of terminally-differentiated HIV-specific CD8+ T cells were mono-functional (median 69% [IQR: 57–83]), producing predominantly CD107a or MIP1β. Moreover, proportions of HIV-specific mono-functional CD8+ T cells positively associated with proportions of terminally-differentiated HIV-specific CD8+ T cells (p=0.019, r=0.54). In contrast, CMV-specific CD8+ T cell polyfunctional capacities were similar across all memory subpopulations, with terminally- and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8+ T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses.
PMCID: PMC3466366  PMID: 22966086
17.  No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial 
PLoS Medicine  2012;9(3):e1001196.
In a three-arm randomized trial conducted among adult patients in HIV treatment centers in The Netherlands, Marlous Grijsen and colleagues examine the effects of temporary combination antiretroviral therapy during primary HIV infection.
The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI).
Methods and Findings
Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm3 or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log10 copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log10 copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0–1.8) y compared to 3.0 (1.9–4.2) and 1.8 (0.5–3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25–0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32–0.95]) were associated with time to (re)start of cART.
In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.
Trial registration
Current Controlled Trials ISRCTN59497461
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, nearly three million people become infected with HIV, the virus that causes AIDS. The first stage of HIV infection—primary HIV infection—lasts a few weeks and often goes undetected, although most individuals develop a short, flu-like illness. During this stage of infection, the immune system begins to make antibodies to HIV. The second stage of HIV infection, which lasts many years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, the immune system is unable to fight off other infections and patients enter the third phase of HIV infection—symptomatic HIV infection. The final stage—AIDS—is characterized by the occurrence of one or more AIDS-defining conditions, which include severe but unusual infections and several types of cancer. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Nowadays, although there is still no cure for HIV infection, HIV has become a chronic disease because of the availability of combination antiretroviral therapy (cART; cocktails of several powerful drugs). This means that many HIV-positive people have a near-normal life span.
Why Was This Study Done?
It is currently recommended that people start cART when their CD4 count falls below 350 CD4 cells per cubic milliliter (cells/mm3) of blood, when they develop severe constitutional symptoms such as fever lasting longer than a month, or when they develop an AIDS-defining condition. But could a short course of cART during primary HIV infection be clinically beneficial? Some, but not all, nonrandomized studies have shown that such treatment reduces the viral set point (the stabilized viral load that is reached after the immune system begins to make antibodies to HIV; the viral load is the amount of virus in the blood) and slows the decline of CD4 cell count in patients. In this randomized trial (the Primo-SHM trial), the researchers assess the clinical benefit of temporary cART initiated during primary HIV infection by measuring its effects on the viral set point and on when patients have to restart cART during chronic HIV infection. In a randomized controlled trial, patients are assigned by the play of chance to receive different treatments and then followed to compare the effects of these treatments.
What Did the Researchers Do and Find?
The researchers assigned 168 patients with primary HIV infection to receive no treatment, 24 weeks of cART, or 60 weeks of cART. They measured the viral set point (the viral load in the blood 36 weeks after randomization in the no treatment arm and 36 weeks after cART interruption in the treatment arms) and determined the time off therapy (the time between randomization and the start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms) for each patient. cART was (re)started following two consecutive CD4 counts below 350 cells/mm3 or when symptomatic HIV disease developed. The average viral set point was lower in the patients who received early cART than in those who had no treatment. Moreover, on average, the patients in the no treatment arm started cART 0.7 years after randomization whereas those in the 24- and 60-week treatment arms restarted cART after 3.0 and 1.8 years, respectively. There was no statistically significant difference between the 24-week and 60-week treatment arms in time off therapy.
What Do These Findings Mean?
These findings suggest that temporary cART during primary HIV infection can transiently lower the viral set point and can delay the need to restart cART during chromic HIV infection. They also suggest that 24 weeks of cART during primary HIV is as effective as 60 weeks of treatment. These findings need to be confirmed in other settings, and follow-up studies are needed to evaluate the long-term benefits of early temporary cART, but given the short time between cART interruption and treatment restart, the researchers suggest that not interrupting early cART, but instead continuing it for life, should be considered. However, they add, because patients are often physically and emotionally distressed at this stage of HIV infection, adherence to cART during primary HIV infection may be suboptimal, and so patients with primary HIV infection should be advised to start cART only when they feel ready to start treatment.
Additional Information
Please access these web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, including information on the clinical progression of HIV infection
NAM/aidsmap provides information about HIV/AIDS, including a factsheet on primary infection
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care and on the stages of HIV infection (in English and Spanish)
The World Health Organization's 2010 antiretroviral therapy guidelines provide recommendations on when to initiate cART
Information about Primo-SHM is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
PMCID: PMC3313945  PMID: 22479156
18.  Acute Plasma Biomarkers of T Cell Activation Set-Point Levels and of Disease Progression in HIV-1 Infection 
PLoS ONE  2012;7(10):e46143.
T cell activation levels, viral load and CD4+ T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-β1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4+ T cell counts at set-point and capable to predict 30% of the CD4+ T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4+ T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4+ T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4+ T cell counts or viremia levels.
PMCID: PMC3462744  PMID: 23056251
19.  Replicative Capacity of Human Immunodeficiency Virus Type 1 Transmitted from Mother to Child Is Associated with Pediatric Disease Progression Rate▿  
Journal of Virology  2009;84(1):492-502.
Human immunodeficiency virus (HIV)-infected infants in the developing world typically progress to AIDS or death within the first 2 years of life. However, a minority progress relatively slowly. This study addresses the potential contribution of viral factors to HIV disease progression in eight infants selected from a well-characterized cohort of C clade HIV-infected infants, monitored prospectively from birth in Durban, South Africa. Three infants were defined as “progressors,” and five were defined as “slow progressors.” We observed that slow-progressor infants carry HIV isolates with significantly lower replicative capacity compared to virus from progressors. Furthermore, our data suggest a link between the attenuated viral phenotype and HLA-B* 57/5801 epitope-specific Gag mutational patterns of the transmitted virus and not to coreceptor usage or to the presence of Nef deletions or insertions. These data underline the importance of virus-host interactions and highlight the contribution of viral attenuation through Gag-specific CD8+ T-cell escape mutations, among other factors, in the control of pediatric HIV infection.
PMCID: PMC2798410  PMID: 19828603
20.  Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects 
Journal of Virology  2012;86(18):9802-9816.
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1 in vivo evolution and epitope-specific CD8+ T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+ T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+ T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+ T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.
PMCID: PMC3446568  PMID: 22761389
21.  HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa 
PLoS Medicine  2012;9(7):e1001245.
Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART.
Methods and Findings
Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results.
Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.
Please see later in the article for the Editors' Summary
Editors' Summary
Following the first reported case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, increased rapidly. In recent years, the number of people becoming newly infected has declined slightly, but the virus continues to spread at unacceptably high levels. In 2010 alone, 2.7 million people became HIV-positive. HIV, which is usually transmitted through unprotected sex, destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, half of HIV-infected people died within eleven years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and, for people living in affluent countries, HIV/AIDS gradually became considered a chronic condition. But because ART was expensive, for people living in developing countries HIV/AIDS remained a fatal condition. Roll-out of ART in developing countries first started in the early 2000s. In 2006, the international community set a target of achieving universal ART coverage by 2010. Although this target has still not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving ART.
Why Was This Study Done?
Several studies suggest that ART, in addition to reducing illness and death among HIV-positive people, reduces HIV transmission. Consequently, there is interest in expanding the provision of ART as a strategy for reducing the spread of HIV (“HIV treatment as prevention"), particularly in sub-Saharan Africa, where one in 20 adults is HIV-positive. It is important to understand exactly how ART might contribute to averting HIV transmission. Several mathematical models that simulate HIV infection and disease progression have been developed to investigate the impact of expanding access to ART on the incidence of HIV (the number of new infections occurring in a population over a year). But, although all these models predict that increased ART coverage will have epidemiologic (population) benefits, they vary widely in their estimates of the magnitude of these benefits. In this study, the researchers systematically compare the predictions of 12 mathematical models of the HIV epidemic in South Africa, simulating the same ART intervention programs to determine the extent to which different models agree about the impact of expanded ART.
What Did the Researchers Do and Find?
The researchers invited groups who had previously developed mathematical models of the epidemiological impact of expanded access to ART in South Africa to participate in a systematic comparison exercise in which their models were used to simulate ART scale-up scenarios in which the CD4 count threshold for treatment eligibility, access to treatment, and retention on treatment were systematically varied. To exclude variation resulting from different model assumptions about the past and current ART program, it was assumed that ART is introduced into the population in the year 2012, with no treatment provision prior to this, and interventions were evaluated in comparison to an artificial counterfactual scenario in which no treatment is provided. A standard scenario based on the World Health Organization's recommended threshold for initiation of ART, although unrepresentative of current provision in South Africa, was used to compare the models. In this scenario, 80% of HIV-infected individuals received treatment, they started treatment on average a year after their CD4 count dropped below 350 cells per microliter of blood, and 85% remained on treatment after three years. The models predicted that, with a start point of 2012, the HIV incidence would be 35%–54% lower in 2020 and 32%–74% lower in 2050 compared to a counterfactual scenario where there was no ART. Estimates of the number of person-years of ART needed per infection averted (the efficiency with which ART reduced new infections) ranged from 6.3–18.7 and from 4.5–20.2 over the periods 2012–2020 and 2012–2050, respectively. Finally, estimates of the impact of ambitious interventions (for example, immediate treatment of all HIV-positive individuals) varied widely across the models.
What Do These Findings Mean?
Although the mathematical models used in this study had different characteristics, all 12 predict that ART, at high levels of access and adherence, has the potential to reduce new HIV infections. However, although the models broadly agree about the short-term epidemiologic impact of treatment scale-up, their longer-term projections (including whether ART alone can eliminate HIV infection) and their estimates of the efficiency with which ART can reduce new infections vary widely. Importantly, it is possible that all these predictions will be wrong—all the models may have excluded some aspect of HIV transmission that will be found in the future to be crucial. Finally, these findings do not aim to indicate which specific ART interventions should be used to reduce the incidence of HIV. Rather, by comparing the models that are being used to investigate the feasibility of “HIV treatment as prevention," these findings should help modelers and policy-makers think critically about how the assumptions underlying these models affect the models' predictions.
Additional Information
Please access these websites via the online version of this summary at
This study is part of the July 2012 PLoS Medicine Collection, Investigating the Impact of Treatment on New HIV Infections
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, on HIV treatment as prevention, and on HIV/AIDS in South Africa (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment (in English, French, and Spanish); its 2010 ART guidelines can be downloaded
The HIV Modelling Consortium aims to improve scientific support for decision-making by coordinating mathematical modeling of the HIV epidemic
Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
PMCID: PMC3393664  PMID: 22802730
22.  Transmitted Virus Fitness and Host T Cell Responses Collectively Define Divergent Infection Outcomes in Two HIV-1 Recipients 
PLoS Pathogens  2015;11(1):e1004565.
Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.
Author Summary
The length of time taken by HIV-1-infected individuals to develop AIDS varies widely depending on how efficiently virus replication is controlled. Although host cellular immune responses are known to play an important role in viral control, the contributions made by the infecting virus and the host antibody response to this process are less clear. To gain insight into this, we performed a detailed analysis of the interplay between the infecting virus and host immune responses in two HIV-1-infected individuals, one of whom controlled virus replication efficiently while the other did not. We found that the virus infecting the HIV-1 controller replicated much less well in culture than that infecting the progressor. The antibody responses made by both subjects were similar, but early after infection the controller mounted a T cell response targeting many sites in the virus, whilst the progressor's T cell response initially targeted only two sites, one of which rapidly mutated to avoid immune recognition. This study highlights the contribution of the replication capacity of the infecting virus and associated early induction of a broad HIV-specific T cell response, which was less readily undermined by rapid viral escape, to viral control in HIV-1 infection.
PMCID: PMC4287535  PMID: 25569444
23.  Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection 
Retrovirology  2008;5:112.
Elite non-progressors (plasma viral load <50 copies/ml while antiretroviral naive) constitute a tiny fraction of HIV-infected individuals. After 12 years follow-up of a cohort of 13 long-term non-progressors (LTNP) identified from 135 individuals with transfusion-acquired HIV infection, 5 remained LTNP after 23 to 26 years infection, but only 3 retained elite LTNP status. We examined the mechanisms that differentiated delayed progressors from LTNP in this cohort.
A survival advantage was conferred on 12 of 13 subjects, who had at least one host genetic factor (HLA, chemokine receptor or TLR polymorphisms) or viral attenuating factor (defective nef) associated with slow progression. However, antiviral immune responses differentiated the course of disease into and beyond the second decade of infection. A stable p24-specific proliferative response was associated with control of viraemia and retention of non-progressor status, but this p24 response was absent or declined in viraemic subjects. Strong Gag-dominant cytotoxic T lymphocyte (CTL) responses were identified in most LTNP, or Pol dominant-CTL in those with nef-defective HIV infection. CTL were associated with control of viraemia when combined with p24 proliferative responses. However, CTL did not prevent late disease progression. Individuals with sustained viral suppression had CTL recognising numerous Gag epitopes, while strong but restricted responses to one or two immunodominant epitopes was effective for some time, but failed to contain viraemia over the course of this study. Viral escape mutants at a HLA B27-restricted Gag-p24 epitope were detected in only 1 of 3 individuals, whereas declining or negative p24 proliferative responses occurred in all 3 concurrent with an increase in viraemia.
Detectable viraemia at study entry was predictive of loss of LTNP status and/or disease progression in 6 of 8, and differentiated slow progressors from elite LTNP who retained potent virological control. Sustained immunological suppression of viraemia was independently associated with preserved p24 proliferative responses, regardless of the strength and breadth of the CTL response. A decline in this protective p24 response preceded or correlated with loss of non-progressor status and/or signs of disease progression.
PMCID: PMC2633348  PMID: 19077215
24.  Alterations in Cardiac and Pulmonary Function in Pediatric Rapid Human Immunodeficiency Virus Type 1 Disease Progressors 
Pediatrics  2000;105(1):e9.
Infants with human immunodeficiency virus type 1 (HIV-1) can be divided into rapid progressors (RPs) and non-rapid progressors (non-RPs) based on symptoms and immunologic status, but detailed information about cardiac and pulmonary function in RP and non-RP children needs to be adequately described.
Cardiac, pulmonary, and immunologic data and HIV-1 RNA burden were periodically measured in 3 groups: group I, 205 vertically infected children enrolled from 1990 to 1994 and followed through 1996; group II, a prospectively studied cohort enrolled at birth that included 93 infected (group IIa); and 463 noninfected infants (group IIb).
Mean respiratory rates were generally higher in group IIa RP than non-RP children throughout the period of follow-up, achieving statistical signifance at 1 month, 12 months, 24 months, 30 months, and 48 months of follow-up. Non-RP and group IIb (HIV-uninfected children) had similar mean respiratory rates from birth to 5 years of age.
Significant differences in mean respiratory rates were found between group I RP and non-RP at 7 age intervals over the first 6 years of life. Mean respiratory rates were higher in RP than in non-RP at <1 year, 2.0 years, 2.5 years, 3.0 years, 3.5 years, 4.0 years, and 6.0 years of age.
Mean heart rates in group IIa RP, non-RP, and group IIb differed at every age. Rapid progressors had higher mean heart rates than non-RP at all ages through 24 months. Mean heart rates at 30 months through 60 months of age were similar for RP and non-RP children. Non-RP children had higher mean heart rates than did group IIb at 8 months, 24 months, 36 months, 42 months, 48 months, 54 months, and 60 months of age.
In group I, RP had higher mean heart rates than non-RP at 2.0 years, 2.5 years, 3.0 years, and 4.0 years of age. After 4 years of age, the non-RP and RP had similar mean heart rates.
Mean fractional shortening differed between the 3 group II subsets (RP, non-RP, and IIb) at 4, 8, 12, 16, and 20 months of age. Although mean fractional shortening was lower in RP than in non-RP in group II at all time points between 1 and 20 months, the mean fractional shortening was significantly lower in RP only at 8 months when restricting the statistical comparisons to the 2 HIV-infected groups (RP and non-RP). Mean fractional shortening increased in the first 8 months of life followed by a gradual decline through 5 years of age among group IIb children. No significant differences among the 3 groups in mean fractional shortening were detected after 20 months of age.
In group I, differences between RP and non-RP in mean fractional shortening were detected at 1.5, 2.0, 2.5, and 3.0 years of age. After 3 years of age, group means for fractional shortening in RP and non-RP did not differ. Because of the limited data from the first months of the group I patients, it could not be determined whether this group experienced the gradual early rise in mean fractional shortening seen in the group II infants.
In group IIa, RP had more clinical (eg, oxygen saturation <96%) and chest radiographic abnormalities (eg, cardiomegaly) at 18 months of life. RP also had significantly higher 5-year cumulative mortality than non-RP, higher HIV-1 viral burdens than non-RP, and lower CD8+ T-cell counts.
Rapid disease progression in HIV-1-infected infants is associated with significant alterations in heart and lung function: increased respiratory rate, increased heart rate, and decreased fractional shortening. The same children exhibited the anticipated significantly increased 5-year cumulative mortality, increased serum HIV-1 RNA load, and decreased CD8+ (cytotoxic) T-cell counts. Measurements of cardiopulmonary function in HIV-1-infected children seem to be useful in the total assessment of HIV-1 disease progression.
PMCID: PMC4331103  PMID: 10617746
25.  Adolescent HIV/AIDS: Issues and challenges 
Adolescence (10-19 years) is a phase of physical growth and development accompanied by sexual maturation, often leading to intimate relationships. Adolescent HIV/AIDS is a separate epidemic and needs to be handled and managed separately from adult HIV. The adolescents can be subdivided into student, slum and street youth; street adolescents being most vulnerable to HIV/AIDS. Among various risk factors and situations for adolescents contracting HIV virus are adolescent sex workers, child trafficking, child labor, migrant population, childhood sexual abuse, coercive sex with an older person and biologic (immature reproductive tract) as well as psychological vulnerability. The most common mode of transmission is heterosexual, yet increasing number of perinatally infected children are entering adolescence. This is due to “bimodal progression” (rapid and slow progressors) among the vertically infected children. Clinically, the HIV infected adolescents present as physically stunted individuals, with delayed puberty and adrenarche. Mental illness and substance abuse are important co-morbidities. The disclosure and declaration of HIV status to self and family is challenging and guilt in sexually infected adolescents and tendency to blame parents if vertically affected need special consideration and proper counseling. Serodiscordance of the twins and difference in disease progression of seroconcordant twins are added causes of emotional trauma. Treatment related issues revolve around the when and what of initiation of ART; the choice of antiretrovirals and their dosages; issues related to long term ADRs; sense of disinhibition following ART commencement; adherence and resistance.
PMCID: PMC3140141  PMID: 21808429
Adolescent; human immunodeficiency syndrome / acquired immunodeficiency syndrome; issues

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