Purpose of review
This review summarizes the development and implementation of a large clinical trial, HIV Prevention Trials Network (HPTN) 052, whose initial results were recently presented and published.
A randomized, clinical trial demonstrated that antiretroviral therapy reduces the sexual transmission of HIV in HIV-serodiscordant couples by more than 96%. The logistical challenges in preparing for and conducting such a trial were considerable.
HPTN 052 required many years of preparation, considerable collaboration between National Institute of Health and six pharmaceutical companies, and careful ongoing consideration of a large number of ethical issues. HPTN 052 revealed the magnitude of benefit when using antiretroviral therapy to prevent the transmission of HIV, and served as proof of a concept. The results have proven central to the development of new global HIV-prevention efforts.
antiretroviral therapy; prevention; transmission
Lymphoma remains a leading cause of mortality in HIV infected patients. In the HIV negative setting high dose therapy with autologous stem cell rescue (ASCT) has been a long accepted treatment for certain malignancies such as lymphoma and leukemia. Early transplant trials excluded older patients, and patients with comorbidities such as HIV infection. However, the procedural related mortality of transplantation has decreased both due to the use of peripheral blood stem cells instead of bone marrow and due to the use of new reduced intensity conditioning regimens. During this same era, the treatment of HIV infection has also become more effective. Patients are no longer dying of opportunistic infections and in addition, their hematologic function has improved.
With these advances in HIV therapy it is possible for HIV infected patients to mobilize adequate numbers of stem cells for an autologous transplant. In addition, with appropriate antiretroviral therapy and infection prophylaxis, the HIV infected patient can tolerate intensive doses of chemotherapy. This review will summarize clinical trials of ASCT in HIV positive patients. Furthermore, the field of solid organ transplantation has grown to also include HIV positive patients. The challenges in solid organ transplantation are similar to allogeneic stem cell transplantation, namely that patients require chronic immunosuppression. This article will also review some of the approaches to allogeneic stem cell transplantation in the HIV positive patient and provide a rationale for the broader use of stem cell transplantation for appropriate HIV related hematologic malignancies.
Autologous transplant; Allogeneic Transplant; Lymphoma
Purpose of review
The purpose of this review is to describe a critical need of the HIV research community for a globally accessible database of HIV vaccine responses that stores data from multiple assay platforms in the form of lists of correlates of immune protection and vaccine efficacy. This is not a detailed review but a first step toward developing a dialogue among investigators and funding organizations to build upon existing resources to efficiently develop a HIV vaccine response and correlates database. We also discuss examples of databases that complement our needs and could be integrated into our proposed database requirements.
Several vaccine-related databases that store information at the study level currently exist, however, at the present time, a correlates of immune protection database does not exist.
Here, we discuss the scientific climate surrounding HIV vaccine development with the evolution of systems biology approaches, the problems at hand for analyzing and harmonizing datasets generated from preclinical and clinical studies, and the curation and accessibility of useful information to model outcomes. We also compare key database requirements of a few existing globally accessible databases and provide several illustrative correlate database submission and utilization examples.
correlates; database; HIV; immune responses; vaccine
Purpose of review
The use of systems biology approaches to understand and predict vaccine-induced immunity promises to revolutionize vaccinology. For centuries vaccines were developed empirically, with very little understanding of the mechanisms by which they mediate protective immunity. The so-called systems vaccinology approach employs high-throughput technologies (e.g. microarrays, RNA-seq and mass spectrometry-based proteomics and metabolomics) and computational modeling to describe the complex interactions between all the parts of immune system, with a view to elucidating new biological rules capable of predicting the behavior of the system.
Systems biology successfully applied to yellow-fever and influenza vaccines has led to the discovery of signatures that predict vaccine immunogenicity, and promises to advance basic immunology research by providing novel mechanistic insights about immune regulation. However a major challenge of systems vaccinology concerns the analyses and interpretation of the large and noisy data sets generated by high-throughput techniques. Overcoming these issues, we envision that systems vaccinology will have a potential impact on vaccine development, including HIV vaccines.
High-throughput technologies allow the investigation of vaccine-induced immune responses at system and molecular levels. These are currently being used to unravel new molecular insights about the immune system, and are on the verge of being integrated into clinical trials to enable rational vaccine design and development.
blood transcriptomics; systems biology; systems vaccinology; vaccinology
Purpose of Review
The recent modest success of the RV144 HIV vaccine trial in Thailand has shown that development of an HIV vaccine is possible. Designing a vaccine that achieves better protection, however, will require a more complete understanding of vaccine mechanisms of action and correlates of protection. Systems biology approaches enable integration of large datasets from a variety of assays and offer new approaches to understanding how vaccine-induced immune responses are coordinately regulated. In this review, we discuss recent advances in clinical trial design, specimen collection, and assay standardization that will generate datasets for systems analyses of immune responses to HIV vaccines.
Several recently-published HIV vaccine trials have shown that different HIV vaccine prime/boost combinations can greatly affect the immune response generated, but mechanistic insights into their modes of action are lacking. Novel systems biology studies of efficacious, licensed vaccines provide a new template for analysis of HIV vaccines. To generate datasets appropriate for systems analysis, current HIV vaccine clinical trials are undergoing design modifications and increased standardization of specimen collection and immune response assays.
Systems biology approaches to HIV vaccine evaluation are driving new methods of HIV vaccine immune response profiling in clinical trials, and will hopefully lead to new improved HIV vaccines in the near future.
HIV vaccine; systems biology; clinical trials; assay standardization
Purpose of review
This review will discuss the use of systems biology approaches to dissect the heterogeneity of the HIV-specific CD8+ T cell response.
New experimental approaches have allowed complex phenotypes of individual cells present in the human antigen-specific CD8+ T cell response to be characterized. Genome-wide measurements of gene expression in antigen-specific T cells have created broad molecular phenotypes of the T cell response to HIV. Pattern recognition algorithms to discover new sub-classes of samples in microarray datasets are becoming increasingly sophisticated. Together, these advances now allow the heterogeneity of the T cell response to HIV to be unraveled.
The phenotype antigen-specific T cells responding to pathogens like HIV in humans is seen as much “noisier” than in animal models of infection. However, applying new systems biology tools may provide an opportunity to identify the sources of this “noise” as novel, biologically distinct sub-classes of CD8+ T cell response to HIV.
HIV; heterogeneity; genomics; single-cell
Purpose of Review
Failure to control viral infections such as HIV, results in TCR and inhibitory receptor driven exhaustion of antigen-specific T cells. Persistent signaling by these receptors during chronic viral infection sculpts the transcriptional regulatory programs of virus-specific T cells. The resulting gene expression profile is tailored to temper the potentially damaging effector functions of cytotoxic T cells and adapt them to an antigen and inflammation rich environment. Here we review recent studies investigating mechanisms of transcriptional regulation of effector, functional memory, and exhausted T cell functions during acute versus chronic infections.
Patterns of gene expression in virus-specific CD8 T cells are a result of a combination of pro and inhibitory signals from antigen presentation (TCR-mediated) and co-inhibitory receptor ligation (PD-1, 2B4). Further, memory-specific transcriptional regulation of 2B4 expression and signaling impose a self-limiting secondary effector response to a prolonged viral infection. Additionally, differentiation of functional memory CD8 T cells is coupled to acquisition of a repressive epigenetic program for PD-1 expression. However, chronic infection provides a signal which blocks the acquisition of these epigenetic modifications reinforcing the suppression of CTL functions in exhausted cells.
Current findings suggest that the mechanism(s) that delineate functional memory versus exhaustion are coupled to acquisition of transcriptional programs at the effector stage of differentiation, reinforced by cessation or persistence of TCR signaling.
Chronic Infection; CD8 T cell; Exhaustion; Transcription Factor; Epigenetic
Purpose of review
Major roadblocks persist in the development of vaccines that elicit potent neutralizing antibodies targeting diverse HIV-1 strains, similar to known broadly neutralizing HIV-1 human monoclonal antibodies. Alternatively, other types of anti-HIV-1 envelope antibodies that may not neutralize HIV-1 in traditional neutralization assays but have other anti-HIV-1 activities (hereafter termed HIV-1 inhibitory antibodies) can be elicited by current vaccine strategies, and numerous studies are exploring their roles in preventing HIV-1 acquisition. We review examples of strategies for eliciting potentially protective HIV-1 inhibitory antibodies.
Heterologous prime-boost strategies can yield anti-HIV immune responses; although only one (canarypox prime, Env protein boost) has been tested and shown positive results in an efficacy trial (RV144). Although the immune correlates of protection are as yet undefined, the reduced rate of acquisition without a significant effect on initial viral loads or CD4+ T cell counts, have raised the hypothesis of an RV144 vaccine-elicited transient protective B cell response.
In light of the RV144 trial, there is a critical need to define the entire functional spectrum of anti-HIV-1 antibodies, how easily each can be elicited, and how effective different types of antibody effector mechanisms can be in prevention of HIV-1 transmission.
Vaccines; B-cells; Neutralizing Antibodies; Inhibitory Antibodies; Mucosal
Purpose of review: describe why this review is timely and relevant
An estimated 33 million people are living with Human Immunodeficiency Virus (HIV) and Universal Access remains a dream for millions of people. By end 2008, 4 million people were on treatment, however, over 5 million needed treatment and in 2007 there were 2.7 million new infections. Without significant improvement in prevention, we are unlikely to meet universal access targets including the growing demand for highly active antiretroviral treatment (HAART). This review examines HAART as a potential tool for preventing HIV transmission
Recent findings: describe the main themes in the literature covered by the article
We discuss recent scientific evidence regarding the treatment and prevention gap, importance viral load and HIV transmission, HAART and HIV transmission, when to start, HIV counseling and testing, modeling results and next steps.
Summary: describe the implications of the findings for clinical practice or research
HAART has considerable treatment and prevention benefits and it needs to be is considered as a key element of combination prevention. To explore HAART as an effective prevention strategy we recommend further evaluation of human rights and ethical considerations, clarification of research priorities and exploration of feasibility and acceptability issues.
HAART; HIV; prevention; universal access; modeling
Purpose of Review
Highly active antiretroviral therapy (HAART) use has markedly reduced AIDS-related mortality and opportunistic illness. With improved survival, cardiovascular disease (CVD) has emerged as an important non-infectious chronic co-morbidity among antiretroviral (ARV)-treated HIV-infected persons.
HIV infection can impact CVD and co-morbidiities known to increase CVD risk. Untreated HIV can cause proatherogenic elevations in serum lipids. Chronic HIV viremia results in increases in systemic inflammation, hypercoagulation, and reductions in endovascular reactivity, all of which are at least partially reversible with virally suppressive HAART. Chronic T cell activation can also result in adverse vascular effects. Use of some ARV drugs can impact CVD risk by causing pro-atherogenic serum lipid elevations, induction of insulin resistance, increases in visceral adiposity or subcutaneous fat loss. Abacavir use may increase myocardial infarction risk by reducing vascular reactivity and/or increasing platelet activation. Traditional risk factors such as advancing age, smoking, hyperlipidemia, and hypertension remain important predictors of CVD among HAART-treated HIV-infected persons.
HIV in the HAART era is a chronic manageable condition. CVD is an important cause of morbidity among HIV-infected persons. Untreated HIV can increase CVD risk in several ways and these effects are at least partially reversible with successful treatment. Use of specific ARV’s can adversely impact CVD risk but the multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have. Standard CVD screening and risk-reducing interventions should be routinely undertaken for HIV-infected persons.
Cardiovascular disease in HIV infection; Inflammation; hypercoagulation; vascular functioning; Effects of antiretroviral drugs; Hyperlipidemia
Purpose of review
To discuss recent advances in our understanding of the diverse roles of NF-κB/Rel family members in HIV-1 latency.
Various NF-κB/Rel family members can reinforce maintenance of HIV-1 latency. For example, p50 recruits histone deacetylase 1 to the HIV-1 long terminal repeat promoting chromatin condensation and reduced RNA Pol II recruitment. Low-level NF-κB activation during homeostatic proliferation of memory CD4 T cells induced by IL-7 and TCR signaling or OX40 action promotes expression of antiapoptotic gene targets like BCL2 and BCLXL. Additionally, the IκB kinase phosphorylates FOXO3a transcription factor, blocking its induction of proapoptotic genes. These combined effects promote memory CD4 T-cell survival, thus maintaining the latent reservoir. Conversely, when the nontumorigenic phorbol ester, prostratin, is combined with histone deacetylase inhibitors, potent synergistic activation of latent HIV-1 occurs involving nuclear expression of NF-κB.
These recent findings highlight both the antagonistic and agonistic effects of the NF-κB signaling pathway on HIV-1 latency. Synergistic inducers acting might be useful for flushing of latent virus from reservoirs in infected patients. The ultimate, albeit lofty, goal is to achieve full viral eradication. However, a more reasonable goal might be a functional cure where patients experience a drug-free remission.
drug-free remission; HIV-1 latency; homeostatic proliferation; NF-κB; viral eradication
Purpose of Review
Up to one third of HIV-infected patients are infected with HCV. It is now widely accepted that HIV accelerates the course of HCV-related chronic liver disease. The improved survival of HIV patients after successful ART has led to a significant decline in HIV-related morbidity, and liver disease caused by HCV infection has emerged as a major threat to the survival of HIV patients. HIV/HCV coinfected patients have a more rapid progression to cirrhosis and its complications than HCV monoinfected patients. Even though the effect of HCV on HIV infection and disease progression is less clear, most advocate early anti-HCV treatment to reduce the risk of chronic liver disease.
Recent studies support current recommendations to begin ART early in the course of HIV infection in order to limit progression of liver disease in co-infected patients. HIV co-infection has a negative impact on HCV pathogenesis, and despite increased risk of drug-related hepatotoxicity, successful response to ART might lessen progression of chronic liver disease and improve response to anti-HCV therapy.
HIV infection affects rate of liver disease progression in those with HCV coinfection. Treatment of HIV may result in slower rates of progression and liver mortality.
HIV; HCV; Coinfection; Natural history; progression
Purpose of review
The goal of this manuscript is to review key recent findings related to the immunopathogenesis of HCV infection, especially in regards to T lymphocytes. It aims to complement other reviews in this issue on the roles of host genetics (IL-28B), acute HCV infection (when disease outcome is determined) and other factors that may influence fibrosis progression (microbial translocation). The main focus is on specific immunity and T cells in the context of success and failure to control viral infection.
This review focuses in on two areas of intense interest in the recent literature: (1) the relationship between the human leukocyte antigen (HLA), class I restricted T cell responses and the evolution of the virus and (2) the role of inhibitory markers on T cells in the immunopathogenesis of HCV. When appropriate, we compare findings from studies of HIV-specific immunity.
From examining the virus and the mutational changes associated with T cell responses and from analyzing the markers on T cells, there have been numerous advances in the understanding of immune evasion mechanisms employed by HCV.
CD8 T-cell; CD4 T-cell; HLA; inhibitory markers
Purpose of review
The purpose of this review is to highlight recent advances in our understanding of host genetic determinants of HIV pathogenesis and to provide a theoretical framework for interpreting these studies in the context of our evolving understanding of HIV immunopathogenesis.
The first genome-wide association analysis of host determinants of HIV pathogenesis and other recent studies evaluating the interaction between killer cell immunoglobulin-like receptors and human leukocyte antigen alleles have implicated both adaptive and innate immune responses in the control of HIV replication. Furthermore, genetic variation associated with the expression of CCR5 and its ligand have been strongly associated with both decreased susceptibility to HIV infection and delayed clinical progression, independent of their effects on viral replication, suggesting a potential role for CCR5 inhibitors as immune-based therapies in HIV disease.
Host factors associated with the control of HIV replication may help identify important targets for vaccine design, while those associated with delayed clinical progression provide targets for future immune-based therapies against HIV infection.
CCR5; HIV pathogenesis; HLA; host genetic variation; KIR
Purpose of review
Myeloid dendritic cells (mDCs) are pivotal players in HIV-1 infection. They promote transmission and spread and at the same time are critical for recognizing HIV-1 and initiating immune responses to fight infection. Notably, their immunostimulatory capabilities can be harnessed to design better HIV-1 vaccines. In this review, advances in these areas of mDC-HIV-1 interactions are summarized.
New insights into HIV-1-induced dysfunction of mDCs and dysfunctional mDC effects on other cell types, as well as novel mechanisms of viral sensing by mDCs and their evasion by HIV-1 have been uncovered. These results emphasize the importance of mDCs in protection against HIV-1 infection. Targeting mDCs with vaccines and tailored adjuvants may improve the quality and anatomical location of elicited immune responses.
Understanding the multiplicity of HIV-1-DC interactions together with the numerous advances in targeted therapy and vaccination will help in the rational design of approaches to treat and block infection.
Myeloid DC; HIV-1; pattern recognition receptors; dysfunction; immunity
Purpose of review
Chronic immune activation is a key factor driving the immunopathogenesis of AIDS. During pathogenic HIV/SIV infections, innate and adaptive antiviral immune responses contribute to the chronic immune activation. In contrast, non-pathogenic SIV infections of natural hosts such as sooty mangabeys (SMs) and African green monkeys (AGMs) are characterized by low immune activation despite similarly high viremia. This review focuses on the role of innate immune responses in SIV infection.
Several studies have examined the role of innate immune responses to SIV as potential drivers of immune activation. The key result of these studies is that both pathogenic SIV infection of macaques and non-pathogenic SIV infections of natural hosts are associated with strong innate immune responses to the virus, high production of type-I interferons by plasmacytoid dendritic cells, and up-regulation of interferon stimulated genes (ISGs). However, SIV-infected SMs and AGMs (but not SIV-infected macaques) rapidly down-modulate the interferon response within 4–6 weeks of infection, thus resulting in a state of limited immune activation during chronic infection.
Studies in nonhuman primates suggest that chronic innate/interferon responses may contribute to AIDS pathogenesis. Further, the ability of natural host species to resolve innate immune responses after infection provides a novel avenue for potential immunotherapy.
Simian Immunodeficiency Virus; SIV; Chronic Immune Activation; Innate Immune Responses; Plasmacytoid Dendritic Cells; Type I Interferon; IFNa; Interferon Stimulated Genes (ISGs)
Purpose of review
Acute HIV-1 infection (AHI) is comprised of the eclipse phase, during which the transmitted virus struggles to avoid eradication and achieve amplification/spread; the expansion phase when virus disseminates and undergoes exponential replication associated with extensive CD4+ T cell destruction; and the containment phase when set-point levels of viremia and immune activation are established. The importance of interactions between HIV-1 and innate responses in determining events throughout AHI is increasingly recognised, and is reviewed here.
During the eclipse phase HIV-1 subverts dendritic cell functions to promote its replication at mucosal sites and employs multiple strategies to minimise control by type 1 interferons. Systemic virus dissemination is associated with widespread activation of innate responses, which fuels HIV-1 replication. To minimise the protective effects of innate responses HIV-1 resists control by natural killer cells and may impair innate regulation of adaptive responses. Innate responses remain chronically activated after HIV-1 containment, which is thought to drive HIV-1 pathogenesis.
Innate responses are pivotal determinants of events at all stages of AHI. Increased understanding of mechanisms involved in innate control of HIV-1 and pathways regulating innate activation during HIV-1 infection could facilitate development of novel approaches to combating this infection.
Human immunodeficiency virus; innate immunity; type 1 interferon; dendritic cell; natural killer cell
Purpose of review
HIV infected cells persisting in the face of highly active antiretroviral therapy (HAART) are arguably the greatest hurdle to eradication of the virus from the body. Complementary strategies aimed at selective killing of infected cells are described.
Pioneered by research in the cancer field, various approaches are under development for selective killing of HIV-infected cells. These include targeted cytotoxic proteins, adoptive cell therapy, cytocidal virotherapy, and targeted non-biological drug carriers.
These developmental efforts may provide a critical complement to antiretroviral therapy in efforts to achieve HIV eradication, or a "functional cure" whereby therapy can be stopped without viral rebound.
antibody-drug conjugates; radioimmunotherapy; immunotoxin; adoptive cell therapy; chimeric antigen receptor; oncolytic virotherapy; targeted liposome
Purpose of Review
Highly Active Antiretroviral Therapy (HAART) has resulted in a marked decrease in AIDS-related conditions and death. With improved survival, cardiovascular disease (CVD), hepatic, renal disease and non-AIDS related cancers represent an increasing burden for HIV infected individuals.
HIV Associated Nephropathy (HIVAN), acute renal injury, HAART, and co-morbid conditions such as Hepatitis C, hypertension and diabetes are among the multiple causes of renal disease. In HIVAN there is incomplete understanding of the interaction of the virus with renal cellsand the host genetics leading to susceptibility to this form of renal dysfunction. There is agreement that a baseline estimate of glomerular filtration (eGFR) should be obtained and that renal function should be monitored during antiretroviral therapy. There is, however no agreement as to the most accurate method of estimating GFR. Renal transplantation has emerged as a feasible and successful modality of management of end stage renal disease (ESRD) in HIV infected individuals.
Kidney disease represents an increasing concern in the care of HIV infected persons although there are questions remaining regarding the pathophysiology of HIVAN. Transplantation, however, can be carried out safely in infected persons with ESRD.
HIV Associated Nephropathy; Estimates of Glomerular filtration; Renal transplantation of HIV infected patients with end stage renal disease; Effects of anitiretroviral drugs upon renal function
Purpose of review
To review new studies and directions regarding infant feeding and HIV-1 transmission.
With antiretroviral drugs and shortened breastfeeding, breast milk HIV-1 transmission risk can be decreased from 16 to less than 5%. In the context of peripartum antiretroviral drugs/short breastfeeding, replacement feeding provides negligible benefit in decreasing the risk of HIV-1/death in contrast to previous studies of no antiretroviral drugs/unlimited breastfeeding in which it offered benefit. One study noted a high risk of infant HIV-1 or death (≥17%) after 4 months, with no difference in risk in infants with shortened breastfeeding versus indefinite breastfeeding. This study suggests that shortened breastfeeding needs caution in implementation. Other African studies have noted minimal risk of HIV-1 or death (<2%) after shortened breastfeeding, underscoring the heterogeneity of infant survival in different settings and the potential to improve infant survival.
Antiretroviral drugs and shortened breastfeeding markedly decrease breastfeeding HIV-1 transmission, shifting the balance to make replacement feeding less beneficial. In some settings shortened breastfeeding poses similar risks as replacement feeding and provides no infant health benefit compared with extended breastfeeding. Programmes aimed at decreasing infant HIV-1 need to do so in the context of promoting infant survival. Strengthening systems to promote infant health is critical.
breastfeeding; HAART; replacement feeding
Purpose of review
To provide an update on the origin of the HIV epidemic and insights into how the immune response is shaping virus evolution.
Characterization of archival samples showed that by the 1960s, HIV had already diverged within humans. It is now estimated that HIV has been in humans since at least the early 1900s. However, despite the potential for different divergent viruses to spread, surprisingly few viruses successfully expanded to cause the global epidemic. In approximately 80% of cases, productive infection is the result of infection with only a single virus or single virus-infected cell. After transmission, HIV evolves at a rapid rate driven by the immune pressure until the virus reaches a delicate survival balance: on one hand avoiding elimination through the development of cytotoxic T-cell immune escape mutations, and on the other sacrificing replication fitness as these mutations may come with a severe fitness cost to the virus. People infected with these ‘attenuated’ cytotoxic T-cell escape viruses can have a survival advantage. Cytotoxic T-cell responses are molding HIV diversity at a population level resulting in a loss of some of the common immune epitopes.
Insights into the origin of HIV and its evolution between populations and within individuals is essential to understanding HIV pathogenesis and imperative for the design of effective biomedical interventions such as vaccines.
CTL escape; HIV evolution; origin; pathogenesis; reversion; transmission
Purpose of review
To understand the role of HIV-specific CD4 T cells in viral control and highlight recent progress in the field.
HIV-specific CD4 T cells show higher functional avidity in elite controllers than in subjects with progressive infection. There is an attrition of the HIV-specific CD4 T cell population in the digestive mucosa of ART-treated subjects that contrasts with robust responses in individuals with spontaneous viral control. Secretion of the cytokine IL-21, by HIV-specific CD4 T cells, is associated with disease control and enhances the capacity of HIV-specific CTL's to suppress viral replication. Studies of the PD-1, IL-10 and Tim-3 pathways provided insight into mechanisms of HIV-specific CD4 T cell exhaustion and new evidence that manipulation of these networks may restore immune functions. Robust, polyfunctional CD4 T cell responses can be elicited with novel HIV and SIV vaccines.
These observations show that HIV-specific CD4 T cell responses are different in elite controllers and individuals with progressive disease. Evidence suggests that HIV-specific CD4 T cells will be an important component of an effective HIV vaccine and significant efforts need to be done to further our understanding of HIV-specific CD4 T cell functions in different body compartments.
HIV; CD4 T cell; elite controllers; IL-21; T cell exhaustion; mucosal immunity
Purpose of review
To discuss recent HIV epidemic models examining the transmission of antiretroviral (ARV) drug resistance.
A relatively small number of recent transmission models have investigated ARV resistance in the context of therapeutic, combined ART (cART); ARV-vaginal microbicides (ARV-VMB); and oral pre-exposure prophylaxis (PrEP). Models of cART use have highlighted potential concerns about future resistance transmission, particularly in resource-constrained settings, and have emphasized the benefits of viral load monitoring in limiting resistance spread. PrEP models have concluded that inadvertent use by HIV-infected individuals could increase resistance prevalence, and that risk compensation by PrEP users could limit their beneficial effects on HIV transmission. ARV-VMB models have demonstrated that while resistance can reduce prophylactic effectiveness in preventing HIV acquisition of female ARV-VMB users, it may concomitantly benefit users' male partners if the resistant strains that female users acquire are less transmissible than wild-type strains. The models have examined the balance between these two factors at the population level.
Recent HIV transmission models have adopted a wide assortment of structures and assumptions to explore drug resistance in the context of different ARV interventions in various settings. There is a need for future work emphasizing the simultaneous effects of multiple ARV interventions, as well as the public health impact of resistance, not just its prevalence.
HIV; mathematical modeling; antiretroviral; resistance; pre-exposure prophylaxis (PrEP); microbicides
1. Purpose of review
HIV is transmitted within complex biobehavioral systems. Mathematical modeling can provide insight to complex population-level outcomes of various behaviors measured at an individual-level.
2. Recent findings
HIV models in the social and behavioral sciences can be categorized in a number of ways; here, we consider two classes of applications common in the field generally, and in the last year in particular: (1) those that explore significant behavioral determinants of HIV disparities within and between populations; and (2) those that seek to evaluate the potential impact of specific social and behavioral interventions.
We discuss two overarching issues we see in the field: the need to further systematize effectiveness models of behavioral interventions, and the need for increasing investigation of the use of behavioral data in epidemic models. We believe that a recent initiative by the National Institutes of Health (NIH) will qualitatively change the relationships between epidemic modeling and sociobehavioral prevention research in the coming years.
Interventions; effectiveness; behavioral data; parameterization
Purpose of Review
Stem cell based strategies for treating HIV infected individuals represent a novel approach toward reconstituting the ravaged immune system with the ultimate aim of clearing the virus from the body. Genetic modification of human hematopoietic stem cells to produce cells that are either resistant to infection, cells that produce lower amounts of infectious virus, or cells that specifically target the immune response against the virus are currently the dominant strategies under development. This review focuses on the understanding of stem cell based approaches that are under investigation and the rationale behind such approaches.
Significant progress has recently been made utilizing stem cell based approaches to treat HIV infection. Ideally, a successful strategy would result in immune clearance of the virus from the body as well long-term restoration of overall immune responses to successfully combat everyday environmental antigens. Two recent clinical trails illustrate how new advances in stem cell based approaches may propel this field forward to clinical reality: one that demonstrates that large-scale gene therapy trials can be performed in a conventional, reproducible manner; and one that demonstrates the utilization of a multi-pronged approach using lentiviral-based gene therapy vectors. These clinical trails serve as the foundation for the development of other technologies, discussed here, that are currently in preclinical development.
Recent advances using stem cell based approaches to treat HIV infection have provided the impetus for a renewed and expanded interest in the development of new cell-based strategies to treat HIV infection as well as a variety of other diseases.
stem cells; gene therapy; HIV therapy; engineered immunity