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1.  Immunity and Hepatitis C: A Review 
Current HIV/AIDS reports  2013;10(1):51-58.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. Due to shared transmission routes, the prevalence of HCV is especially high among individuals infected with HIV. HIV uninfected individuals spontaneously clear HCV approximately 30% of the time, while the rate of control in HIV infected individuals who subsequently acquire HCV is substantially lower. In addition, complications of HCV are more frequent in those with HIV infection, making liver disease the leading cause of non-AIDS-related death in HIV infected individuals. This review summarizes recent advances in understanding the role of the innate and adaptive immune responses to HCV in those with and without HIV. Further defining the interaction between hepatitis C and the host immune system will potentially reveal insights into HCV pathogenesis and the host’s ability to prevent persistent infection, as well as direct the development of vaccines.
doi:10.1007/s11904-012-0146-4
PMCID: PMC3567217  PMID: 23180007
Hepatitis C; HCV; viral hepatitis; hepatitis; Immunity; innate immune response; Interferons; IFN; cellular immunity; adaptive immune response; neutralizing antibodies; chronic infection; acute infection; liver disease; spontaneous clearance; treatment response; SVR; vaccination; HIV; HIV-HCV coinfection; coinfection; T cell response; B cell response; interleukin 18; interleukin 28B; virus
2.  Mechanisms of Host Resistance Against HIV Infection and Progression to AIDS 
Since the discovery in the early eighties of the Human Immunodeficiency Virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), there have been reports of people who were completely resistant to infection with HIV and others who progressed at slower rates to AIDS. The present article summarises the mechanisms involved in resistance against HIV infection and progression to AIDS. The paper will specifically focus on the role of immunological mechanisms, genetics, ethnicity and cultural practices such as male circumcision in mitigating infection. The current understanding on host natural resistance against HIV infection and progression to AIDS would potentially contribute to better prevention strategies, delayed onset of AIDS in people living with HIV, the identification of more efficient types of therapy for AIDS patients and, possibly, appropriate vaccines against HIV/AIDS. This area of research has important implications for patient care through controlling factors that contribute to AIDS progression.
PMCID: PMC3074872  PMID: 21748089
HIV; AIDS; Resistance, Natural; Disease, Progression
3.  Biology of HIV Mucosal Transmission 
Current opinion in HIV and AIDS  2008;3(5):534-540.
Purpose of review
HIV-1 mucosal transmission plays a critical role in HIV-1 infection and AIDS pathogenesis. This review summarizes the latest advances in biological studies of HIV-1 mucosal transmission, highlighting the implications of these studies in the development of microbicides to prevent HIV-1 transmission.
Recent findings
New studies of initial HIV-1 infection using improved culture models updated the current view of mucosal transmission. Mechanistic studies enhanced our understanding of cell-cell transmission of HIV-1 mediated by the major target cells, including dendritic cells, CD4+ T cells, and macrophages. Increasing evidence indicated the significance of host factors and immune responses in HIV-1 mucosal infection and transmission.
Summary
Recent progress in HIV-1 mucosal infection and transmission enriches our knowledge of virus-host interactions and viral pathogenesis. Functional studies of HIV-1 interactions with host cells can provide new insights into the design of more effective approaches to combat HIV-1 infection and AIDS.
doi:10.1097/COH.0b013e32830634c6
PMCID: PMC2542876  PMID: 18802490
HIV; mucosal; transmission; infection; biology
4.  Occult hepatitis B virus infection: A major concern in HIV-infected patients 
Hepatitis Monthly  2011;11(1):7-10.
Human immunodeficiency virus (HIV)- infected patients are at risk of acquiring viral hepatitis, due to common routes of transmission. As the introduction of highly active antiretroviral therapy (HAART) reduced the frequency of opportunistic infections and improved survival, viral hepatitis emerged as an important cause of morbidity and mortality in HIV-infected cases. Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection without detectable hepatitis B surface antigen (HBsAg). There are conflicting reports on the impact of occult HBV infection on the natural history of HIV disease. In this review, we described the findings of studies on HIV and hepatitis B co-infection with focus on the prevalence of occult HBV infection. The results of this review demonstrated the importance of prevention, diagnosis and treatment of occult HBV infection in HIV-positive patients.
PMCID: PMC3206662  PMID: 22087108
Human immunodeficiency virus; Hepatitis B virus; Hepatitis C virus
5.  Towards an HIV cure: science and debate from the International AIDS Society 2013 symposium 
Retrovirology  2013;10:134.
The International AIDS Society convened the multi-stakeholder “Towards an HIV Cure” symposium in Kuala Lumpur, Malaysia in 2013 to address the significant research challenges posed by the search for a cure for HIV infection. Current antiretroviral regimens select for a small reservoir of cells that harbour latent HIV provirus, produce few or no HIV virions, and resist detection or clearance by host immunity. The symposium examined basic molecular science and animal model data, and emerging and ongoing clinical trial results to prioritise strategies and determine the viral and immune responses that could lead to HIV remission without ART. Here we review the presentations that scrutinized the molecular mechanisms controlling virus expression from proviral DNA, and the intrinsic cellular restriction and immune mechanisms preventing viral production. Insights from the basic science have translated into new therapeutic strategies seeking HIV remission without ongoing therapy, and much interest was focused on these ongoing trials. We also summarise the emerging ethical issues and patient expectations as concepts move into the clinic.
doi:10.1186/1742-4690-10-134
PMCID: PMC3828479  PMID: 24224983
6.  HIV-1 Continues To Replicate and Evolve in Patients with Natural Control of HIV Infection ▿ †  
Journal of Virology  2010;84(24):12971-12981.
Elucidating mechanisms leading to the natural control of HIV-1 infection is of great importance for vaccine design and for understanding viral pathogenesis. Rare HIV-1-infected individuals, termed HIV-1 controllers, have plasma HIV-1 RNA levels below the limit of detection by standard clinical assays (<50 to 75 copies/ml) without antiretroviral therapy. Although several recent studies have documented persistent low-grade viremia in HIV-1 controllers at a level not significantly different from that in HIV-1-infected individuals undergoing treatment with combination antiretroviral therapy (cART), it is unclear if plasma viruses are undergoing full cycles of replication in vivo or if the infection of new cells is completely blocked by host immune mechanisms. We studied a cohort of 21 HIV-1 controllers with a median level of viremia below 1 copy/ml, followed for a median of 11 years. Less than half of the cohort carried known protective HLA types (B*57/27). By isolating HIV-1 RNA from large volumes of plasma, we amplified single genome sequences of both pro-rt and env longitudinally. This study is the first to document that HIV-1 pro-rt and env evolve in this patient group, albeit at rates somewhat lower than in HIV-1 noncontrollers, in HLA B*57/27-positive, as well as HLA B*57/27-negative, individuals. Viral diversity and adaptive events associated with immune escape were found to be restricted in HIV-1 controllers, suggesting that replication occurs in the face of less overall immune selection.
doi:10.1128/JVI.00387-10
PMCID: PMC3004307  PMID: 20926564
7.  Frequent Detection of Escape from Cytotoxic T-Lymphocyte Recognition in Perinatal Human Immunodeficiency Virus (HIV) Type 1 Transmission: the Ariel Project for the Prevention of Transmission of HIV from Mother to Infant 
Journal of Virology  1999;73(5):3975-3985.
Host immunologic factors, including human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL), are thought to contribute to the control of HIV type 1 (HIV-1) replication and thus delay disease progression in infected individuals. Host immunologic factors are also likely to influence perinatal transmission of HIV-1 from infected mother to infant. In this study, the potential role of CTL in modulating HIV-1 transmission from mother to infant was examined in 11 HIV-1-infected mothers, 3 of whom transmitted virus to their offspring. Frequencies of HIV-1-specific human leukocyte antigen class I-restricted CTL responses and viral epitope amino acid sequence variation were determined in the mothers and their infected infants. Maternal HIV-1-specific CTL clones were derived from each of the HIV-1-infected pregnant women. Amino acid substitutions within the targeted CTL epitopes were more frequently identified in transmitting mothers than in nontransmitting mothers, and immune escape from CTL recognition was detected in all three transmitting mothers but in only one of eight nontransmitting mothers. The majority of viral sequences obtained from the HIV-1-infected infant blood samples were susceptible to maternal CTL. These findings demonstrate that epitope amino acid sequence variation and escape from CTL recognition occur more frequently in mothers that transmit HIV-1 to their infants than in those who do not. However, the transmitted virus can be a CTL susceptible form, suggesting inadequate in vivo immune control.
PMCID: PMC104176  PMID: 10196293
8.  Epidemiology and interactions of Human Immunodeficiency Virus – 1 and Schistosoma mansoni in sub-Saharan Africa 
Human Immunodeficiency Virus-1/AIDS and Schistosoma mansoni are widespread in sub-Saharan Africa and co-infection occurs commonly. Since the early 1990s, it has been suggested that the two infections may interact and potentiate the effects of each other within co-infected human hosts. Indeed, S. mansoni infection has been suggested to be a risk factor for HIV transmission and progression in Africa. If so, it would follow that mass deworming could have beneficial effects on HIV-1 transmission dynamics. The epidemiology of HIV in African countries is changing, shifting from urban to rural areas where the prevalence of Schistosoma mansoni is high and public health services are deficient. On the other side, the consequent pathogenesis of HIV-1/S. mansoni co-infection remains unknown. Here we give an account of the epidemiology of HIV-1 and S. mansoni, discuss co-infection and possible biological causal relationships between the two infections, and the potential impact of praziquantel treatment on HIV-1 viral loads, CD4+ counts and CD4+/CD8+ ratio. Our review of the available literature indicates that there is evidence to support the hypothesis that S. mansoni infections can influence the replication of the HIV-1, cell-to-cell transmission, as well as increase HIV progression as measured by reduced CD4+ T lymphocytes counts. If so, then deworming of HIV positive individuals living in endemic areas may impact on HIV-1 viral loads and CD4+ T lymphocyte counts.
doi:10.1186/2049-9957-2-2
PMCID: PMC3707091  PMID: 23849678
Schistosoma mansoni; HIV-1; Co-infections; Immunological interactions; Deworming
9.  Mucosal Immunity to HIV: A Review of Recent Literature 
Current opinion in HIV and AIDS  2008;3(5):541-547.
Purpose of review
This review summarizes recent literature in the field of mucosal immunology as it applies to human immunodeficiency virus (HIV) transmission and pathogenesis.
Recent findings
Pertinent recent findings include elucidation of the role of mucosal antigen-presenting cells and retinoic acid in imprinting a gut-homing phenotype on antigen-specific T and B cells, and the identification of Th17 and Treg cells as key modulators of the balance between tolerance and inflammation in mucosal tissues.
Summary
Mucosal surfaces of the body serve as the major portal of entry for human immunodeficiency virus (HIV). These tissues also house a majority of the body's lymphocytes, including the CD4+ T-cells that are the major cellular target for HIV infection. Elucidating mucosal immune responses is critical to our understanding of the host-pathogen relationship for two reasons: first, mucosal barriers are defended by a range of innate and adaptive defenses that might be exploited to develop effective vaccines and/or microbicides; second, adaptive immune responses in mucosal lymphoid tissues may serve to limit viral replication, decreasing the host's viral burden as well as reducing the likelihood of sexual transmission to a naïve host.
doi:10.1097/COH.0b013e32830ab9ee
PMCID: PMC2659331  PMID: 19373019
CTL; gut; IgA; Treg; Th17
10.  Syphilis and human immunodeficiency virus co-infection. 
Co-infection of syphilis and AIDS has profound implications for the African American community. The purpose of this review is to: evaluate the historical background of HIV and syphilis and their similarities in pathogenesis; review the epidemiology of syphilis and HIV co-infection, and implications for continued prevention efforts; examine the effect of syphilis on HIV transmission and acquisition; and, to examine the effects of HIV infection on syphilis transmission, diagnostic and serologic changes, clinical course, and treatment. The prevalence of HIV is higher in those with syphilis; moreover, the prevalence of HIV and syphilis co-infection is highest in African Americans. There may be humoral and cellular immune similarities. HIV may affect the transmission of syphilis, alter its serologic diagnosis, and accelerate and change the clinical course and response to treatment. In conclusion, combined infection of HIV and syphilis may alter the clinical presentation and course of either disease. There are historical and immunologic similarities and the high prevalence in African Americans compared to other groups is of great importance for prevention efforts.
PMCID: PMC2594513  PMID: 12793793
11.  Host Factors and HIV-1 Replication: Clinical Evidence and Potential Therapeutic Approaches 
HIV and human defense mechanisms have co-evolved to counteract each other. In the process of infection, HIV takes advantage of cellular machinery and blocks the action of the host restriction factors (RF). A small subset of HIV+ individuals control HIV infection and progression to AIDS in the absence of treatment. These individuals known as long-term non-progressors (LNTPs) exhibit genetic and immunological characteristics that confer upon them an efficient resistance to infection and/or disease progression. The identification of some of these host factors led to the development of therapeutic approaches that attempted to mimic the natural control of HIV infection. Some of these approaches are currently being tested in clinical trials. While there are many genes which carry mutations and polymorphisms associated with non-progression, this review will be specifically focused on HIV host RF including both the main chemokine receptors and chemokines as well as intracellular RF including, APOBEC, TRIM, tetherin, and SAMHD1. The understanding of molecular profiles and mechanisms present in LTNPs should provide new insights to control HIV infection and contribute to the development of novel therapies against AIDS.
doi:10.3389/fimmu.2013.00343
PMCID: PMC3807056  PMID: 24167505
human immunodeficiency virus; nonprogressors; APOBEC; TRIM; tetherin; SAMHD1; chemokine receptors; chemokine
12.  Risks for HIV, HBV, and HCV infections among male injection drug users in northern Vietnam: A case-control study 
AIDS care  2009;21(1):7-16.
Injection drug use (IDU) and HIV infection are important public health problems in Vietnam. The IDU population increased 70% from 2000 to 2004 and is disproportionately affected by HIV and AIDS--the country’s second leading cause of death. Hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes with HIV and cause serious medical consequences. This study aimed to determine risk factors for acquisition of HIV, HBV, and HCV infections among IDUs in a northern province. We conducted a matched case-control study among active IDUs aged 18–45 who participated in a community-based survey (30-minute interview and serologic testing). Each HIV-infected IDU (case) was matched with one HIV-uninfected IDU (control) by age, sex (males only), and study site (128 pairs). Similar procedures were used for HBV infection (50 pairs) and HCV infection (65 pairs). Conditional logistic regression models were fit to identify risk factors for each infection. Among 309 surveyed IDUs, the HIV, HBV, and HCV prevalence was 42.4%, 80.9%, and 74.1%, respectively. Only 11.0% reported having been vaccinated against hepatitis B. While 13.3% of the IDUs reported sharing needles (past 6 months), 63.8% engaged in indirect sharing practices (past 6 months), including sharing drug solutions, containers, rinse water, and frontloading drugs. In multivariable models, sharing drugs through frontloading was significantly associated with HIV infection (odds ratio [OR] = 2.8), HBV infection (OR = 3.8), and HCV infection (OR = 4.6). We report an unrecognized association between sharing drugs through frontloading and higher rates of HIV, HBV and HCV infections among male IDUs in Vietnam. This finding may have important implications for bloodborne viral prevention for IDUs in Vietnam.
doi:10.1080/09540120802017610
PMCID: PMC2869448  PMID: 19085215
HIV; hepatitis B virus; hepatitis C virus; Vietnam; substance abuse
13.  Natural SIV Hosts: Showing AIDS the Door 
Science (New York, N.Y.)  2012;335(6073):10.1126/science.1217550.
Many species of African nonhuman primates are naturally infected with Simian Immunodeficiency Viruses (SIVs) in the wild and in captivity. In contrast to HIV-infected humans, these natural SIV hosts typically do not develop AIDS despite chronic infection with a highly replicating virus. In this review, we will discuss the most recent advances on the mechanisms of protection from disease progression in natural SIV hosts, with emphasis on how they differ from pathogenic HIV/SIV infections of humans and rhesus macaques. These mechanisms include: i) resolution of immune activation following acute infection; ii) restricted pattern of target cell infection; and iii) protection from mother-to-infant transmission. We highlight the areas that should be pursued in future studies, focusing on potential applications for the treatment and prevention of HIV infection.
doi:10.1126/science.1217550
PMCID: PMC3822437  PMID: 22403383
14.  Elite Control of HIV Infection: Implications for Vaccine Design 
Background
A T cell vaccine that lowers levels of HIV replication could significantly diminish the burden of the AIDS epidemic by attenuating disease progression and reducing the risk of HIV transmission. In order to learn which immune responses an effective HIV vaccine should elicit, we must first identify correlates of immune protection in vivo.
Objective
“Elite controllers” are rare HIV-infected individuals who are able to spontaneously control HIV replication without medication, maintaining viral loads that are consistently below the limits of detection by currently available commercial assays. The objective of this review is to examine studies of elite controllers that may help to elucidate mechanisms of HIV immune control that will be useful in designing a vaccine.
Methods
This review examines recent literature on HIV controllers as well as studies that have evaluated aspects of viral and host immunology that correlate with viral control.
Results/Conclusions
Although many elements of both innate and adaptive immunity are associated with control of HIV infection, the specific mechanism(s) by which HIV elite controllers achieve control remain undefined. Ongoing studies of elite controllers, including those examining host genetic polymorphisms, should facilitate the definition of an effective HIV-specific immune response and guide HIV vaccine design.
doi:10.1517/14712590802571928
PMCID: PMC3731764  PMID: 19063693
Acquired Immune Deficiency Syndrome (AIDS); CD8+ T cell; CD4+ T cell; Human leucocyte antigen (HLA); Cell mediated immunity; Elite controller; Human Immunodeficiency Virus (HIV); Review; Simian Immunodeficiency Virus (SIV); Vaccine; Viral load
15.  Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen. 
Clinical Microbiology Reviews  1995;8(1):87-112.
The lentivirus feline immunodeficiency virus (FIV) is a widespread pathogen of the domestic cat that is mainly transmitted through bites, although other means of transmission are also possible. Its prevalence ranges from 1 to 10% in different cat populations throughout the world, thus representing a large reservoir of naturally infected animals. FIV resembles the human immunodeficiency virus (HIV) in many respects. Similarities include the structural features of the virion, the general organization and great variability of the genome, the life cycle in the infected host, and most importantly, the pathogenic potential. Infection is associated with laboratory signs of immunosuppression as well as with a large variety of superinfections, tumors, and neurological manifestations. Our understanding of FIV is steadily improving and is providing important clues to the pathogenesis of immunodeficiency-inducing lentiviruses. The cellular receptor for FIV is different from the feline equivalent of the human CD4 molecule used by HIV; nevertheless, the major hallmark of infection is a progressive loss of CD4+ T lymphocytes as in HIV infection. The mechanisms by which FIV escapes the host's immune responses are being actively investigated. FIV causes lysis of infected T cells and also appears to predispose these cells to apoptosis. Infection of macrophages and other cell types has also been documented. For reasons yet to be understood, antibody-mediated neutralization of fresh FIV isolates is very inefficient both in vitro and in vivo. Vaccination studies have provided some encouraging results, but the difficulties encountered appear to match those met in HIV vaccine development. FIV susceptibility to antiviral agents is similar to that of HIV, thus providing a valuable system for in vivo preclinical evaluation of therapies. It is concluded that in many respects FIV is an ideal model for AIDS studies.
PMCID: PMC172850  PMID: 7704896
16.  Role of Human Immunodeficiency Virus (HIV)-Specific T-Cell Immunity in Control of Dual HIV-1 and HIV-2 Infection▿  
Journal of Virology  2007;81(17):9061-9071.
Progressive immune dysfunction and AIDS develop in most cases of human immunodeficiency virus type 1 (HIV-1) infection but in only 25 to 30% of persons with HIV-2 infection. However, the natural history and immunologic responses of individuals with dual HIV-1 and HIV-2 infection are largely undefined. Based on our previous findings, we hypothesized that among patients with dual infection the control of HIV-1 is associated with the ability to respond to HIV-2 Gag epitopes and to maintain HIV-specific CD4+ T-cell responses. To test this, we compared the HIV-specific ex vivo IFN-γ enzyme-linked immunospot (ELISPOT) assay responses of 19 dually infected individuals to those of persons infected with HIV-1 or HIV-2 only. Further, we assessed the functional profile of HIV Gag-specific CD4+ and CD8+ T cells from nine HIV dually infected patients by using a multicolor intracellular cytokine staining assay. As determined by ELISPOT assay, the magnitude and frequency of IFN-γ-secreting T-cell responses to gene products of HIV-1 were higher than those to gene products of HIV-2 (2.64 versus 1.53 log10 IFN-γ spot-forming cells/106 cells [90% versus 63%, respectively].) Further, HIV-1 Env-, Gag-, and Nef- and HIV-2 Gag-specific responses were common; HIV-2 Nef-specific responses were rare. HIV-specific CD4+ T helper responses were detected in nine of nine dually infected subjects, with the majority of these T cells producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and, to a lesser extent, interleukin-2. The HIV-1 plasma viral load was inversely correlated with HIV-2 Gag-specific IFN-γ-/TNF-α-secreting CD4+ and HIV-2 Gag-specific IFN-γ-secreting CD8+ T cells. In conclusion, the T-cell memory responses associated with containment of single HIV-1 and HIV-2 infection play a similar significant role in the immune control of dual HIV-1 and HIV-2 infection.
doi:10.1128/JVI.00117-07
PMCID: PMC1951418  PMID: 17582003
17.  Nef Proteins from Simian Immunodeficiency Virus-Infected Chimpanzees Interact with p21-Activated Kinase 2 and Modulate Cell Surface Expression of Various Human Receptors 
Journal of Virology  2004;78(13):6864-6874.
The accessory Nef protein allows human immunodeficiency virus type 1 (HIV-1) to persist at high levels and to cause AIDS in infected humans. The function of HIV-1 group M subtype B nef alleles has been extensively studied, and a variety of in vitro activities believed to be important for viral pathogenesis have been established. However, the function of nef alleles derived from naturally simian immunodeficiency virus (SIV)-infected chimpanzees, the original host of HIV-1, or from the HIV-1 N and O groups resulting from independent zoonotic transmissions remains to be investigated. In the present study we demonstrate that SIVcpz and HIV-1 group N or O nef alleles down-modulate CD4, CD28, and class I or II MHC molecules and up-regulate surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II. Furthermore, the ability of Nef to interact with the p21-activated kinase 2 was generally conserved. The functional activity of HIV-1 group N and O nef genes did not differ significantly from group M nef alleles. However, SIVcpz nef genes as a group showed a 1.8- and 2.0-fold-higher activity in modulating CD28 (P = 0.0002) and Ii (P = 0.016) surface expression, respectively, but were 1.7-fold less active in down-regulating MHC class II molecules (P = 0.006) compared to HIV-1 M nef genes. Our finding that primary SIVcpz nef alleles derived from naturally infected chimpanzees modulate the surface expression of various human cellular receptors involved in T-cell activation and antigen presentation suggests that functional nef genes helped the chimpanzee virus to persist efficiently in infected humans immediately after zoonotic transmission.
doi:10.1128/JVI.78.13.6864-6874.2004
PMCID: PMC421647  PMID: 15194762
18.  Up-Regulation of TLR2 and TLR4 in Dendritic Cells in Response to HIV Type 1 and Coinfection with Opportunistic Pathogens 
AIDS Research and Human Retroviruses  2011;27(10):1099-1109.
Abstract
The ability to trigger an innate immune response against opportunistic pathogens associated with HIV-1 infection is an important aspect of AIDS pathogenesis. Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens, but in HIV-1 patients coinfected with opportunistic infections, the regulation of TLR expression has not been studied. In this context, we have evaluated the expression of TLR2 and TLR4 in monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells of HIV-1 patients with or without opportunistic infections. Forty-nine HIV-1-infected individuals were classified according to viral load, highly active antiretroviral therapy (HAART), and the presence or absence of opportunistic infections, and 21 healthy subjects served as controls. Increased expression of TLR2 and TLR4 was observed in myeloid dendritic cells of HIV-1 patients coinfected with opportunistic infections (without HAART), while TLR4 increased in plasmacytoid dendritic cells, compared to both HIV-1 without opportunistic infections and healthy subjects. Moreover, TLR2 expression was higher in patients with opportunistic infections without HAART and up-regulation of TLR expression in HIV-1 patients coinfected with opportunistic infections was more pronounced in dendritic cells derived from individuals coinfected with Mycobacterium tuberculosis. The results indicate that TLR expression in innate immune cells is up-regulated in patients with a high HIV-1 load and coinfected with opportunistic pathogens. We suggest that modulation of TLRs expression represents a mechanism that promotes HIV-1 replication and AIDS pathogenesis in patients coinfected with opportunistic pathogens.
doi:10.1089/aid.2010.0302
PMCID: PMC3482873  PMID: 21406030
19.  Immunopathogenesis of feline immunodeficiency virus infection in the fetal and neonatal cat 
The global incidence of pediatric HIV infection is estimated at 2.3 million children, most acquiring the infection from their mothers in utero, peripartum, or postpartum. Pediatric HIV infection typically causes a rapidly progressive disease when compared with adult infection, due in part to the profound susceptibility of the neonatal thymus to productive infection or degenerative changes. Failed production of naïve T-lymphocytes further limits the success of antiviral therapy to restore immunologic function. In this review, we explore the use of feline immunodeficiency virus (FIV) infection of domestic cats as an animal model for pediatric HIV infection. Cats infected with FIV represent the smallest host of a naturally occurring lentivirus, and the immunodeficiency syndrome elicited by FIV infection is similar to that of HIV-AIDS. The feline-FIV model uniquely reproduces several key aspects of immunosuppressive lentivirus infection of the thymus, allowing investigators to define viral determinants of pathogenicity, influence of host age on disease outcome, and therapeutic strategies to restore thymus function.
PMCID: PMC2278015  PMID: 17485330
AIDS; FIV; Animal Model; Vertical Transmission; HIV; Feline; Thymus; Review
20.  Virological, Immune and Host genetics Markers in the Control of HIV Infection 
Disease markers  2009;27(3-4):105-120.
HIV infection, if left untreated, leads in most cases to the development of wide immune deterioration, opportunistic infections and eventually AIDS and death. The identification of individuals who despite persisting infection show no or few signs of HIV disease progression has spurred hopes that an effective HIV vaccine could be attainable. The design of such a vaccine will greatly depend on the precise definition of disease markers, host genetic and immune characteristics that mediate relative in vivo control of this virus. Accordingly, a number of viral factors and host genetic characteristics have been shown to play a crucial role in the control of HIV disease by delaying progression to AIDS or even preventing infection. There is also an improved understanding of humoral and cellular immune responses in terms of specificity, functional repertoire, longevity and tissue distribution and their ability to contain HIV replication. However, the definition of good immune correlates unequivocally and causally associated with protection or disease progression remains elusive. Here we review work on viral factors, host genetic markers and immunological determinants that have been identified in individuals with superior control of HIV infection or in subjects who remain uninfected despite frequent exposure to the viral pathogen.
doi:10.3233/DMA-2009-0655
PMCID: PMC3835054  PMID: 19893207
HIV-1; long-term non-progressors (LTNP); Elite Controllers (EC); Highly exposed persistently seronegatives (HEPS); CCR5; CTL; Innate immunity; HIV control; immune correlates; HLA allele frequency
21.  Breaking Barriers to an AIDS Model with Macaque-Tropic HIV-1 Derivatives 
Biology : open access journal  2012;1(2):134-164.
The development of an animal model of human immunodeficiency virus type 1 (HIV-1)/AIDS that is suitable for preclinical testing of antiretroviral therapy, vaccines, curative strategies, and studies of pathogenesis has been hampered by the human-specific tropism of HIV-1. Although simian immunodeficiency virus (SIV) or HIV-1/SIV chimeric viruses (SHIVs)-rhesus macaque models are excellent surrogates for AIDS research, the genetic differences between SIV or SHIV and HIV-1 limit their utility as model systems. The identification of innate retro viral restriction factors has increased our understanding about blockades to HIV-1 replication in macaques and provided a guide for the construction of macaque-tropic HIV-1 clones. However, while these viruses replicate in macaque cells in vitro, they are easily controlled and have not caused AIDS in host animals, indicating that we may not fully understand the restrictive barriers of innate immunity. In this review, we discuss recent findings regarding HIV-1 restriction factors, particularly as they apply to cross-species transmission of primate lentiviruses and the development of a macaque model of HIV-1/AIDS.
doi:10.3390/biology1020134
PMCID: PMC3546514  PMID: 23336082
HIV-1; SIV; Macaca nemestrina; AIDS; cross-species; tropism; innate restriction
22.  Resting CD4+ T Cells from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals Carry Integrated HIV-1 Genomes within Actively Transcribed Host Genes 
Journal of Virology  2004;78(12):6122-6133.
Resting CD4+ T-cell populations from human immunodeficiency virus type 1 (HIV-1)-infected individuals include cells with integrated HIV-1 DNA. In individuals showing suppression of viremia during highly active antiretroviral therapy (HAART), resting CD4+ T-cell populations do not produce virus without cellular activation. To determine whether the nonproductive nature of the infection in resting CD4+ T cells is due to retroviral integration into chromosomal regions that are repressive for transcription, we used inverse PCR to characterize the HIV-1 integration sites in vivo in resting CD4+ T cells from patients on HAART. Of 74 integration sites from 16 patients, 93% resided within transcription units, usually within introns. Integration was random with respect to transcriptional orientation relative to the host gene and with respect to position within the host gene. Of integration sites within well-characterized genes, 91% (51 of 56) were in genes that were actively expressed in resting CD4+ T cells, as directly demonstrated by reverse transcriptase PCR (RT-PCR). These results predict that HIV-1 sequences may be included in the primary transcripts of host genes as part of rapidly degraded introns. RT-PCR experiments confirmed the presence of HIV-1 sequences within transcripts initiating upstream of the HIV-1 transcription start site. Taken together, these results demonstrate that HIV-1 genomes reside within actively transcribed host genes in resting CD4+ T cells in vivo.
doi:10.1128/JVI.78.12.6122-6133.2004
PMCID: PMC416493  PMID: 15163705
23.  Alterations of Natural Killer Cell and T-Lymphocyte Counts in Adults Infected with Human Immunodeficiency Virus through Blood and Plasma Sold in the Past in China and in Whom Infection Has Progressed Slowly over a Long Period 
Natural killer (NK) cells, natural killer T (NKT) cells, and T lymphocytes were analyzed by using a flow cytometer in 225 human immunodeficiency virus (HIV)-positive individuals infected through the past sale of blood and plasma without receiving antiretroviral therapy in the People’s Republic of China. According to CD4 T-cell counts these HIV-infected adults were stratified into three groups: long-term slow progressors, HIV-infected subjects, and AIDS patients. NK cell counts in long-term slow progressors were higher compared to HIV infection and AIDS patients (P < 0.05) and lower compared to normal controls (P < 0.05), whereas NKT cell counts in slow progressors and the HIV infection group were not different from those of normal controls. NK cell counts in HIV-seropositive subjects were positively correlated with CD4 T-cell counts (P < 0.05), and NKT cell counts were positively correlated with CD4 T-cell and CD8 T-cell counts (P < 0.05). The CD8 T-cell counts were higher in slow progressors compared to those with HIV infection, AIDS patients, and normal controls. These results indicated that HIV infection causes alterations of NK cells and T cells in slow progressors, HIV-infected subjects, and AIDS patient groups, but no difference was found in NKT cell counts and percentages in slow progressors and the HIV-infected group compared to normal controls.
doi:10.1128/CDLI.12.11.1275-1279.2005
PMCID: PMC1287755  PMID: 16275940
24.  Hepatocellular carcinoma in patients co-infected with hepatitis C virus and human immunodeficiency virus 
World Journal of Hepatology  2013;5(6):323-327.
Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share a common route of transmission so that about one third of HIV infected individuals show HCV co-infection. Highly active antiretroviral therapy has offered a longer and better life to infected patients. While has removed AIDS-related diseases from the list of most common causes of death their place has been taken by complications of HCV infection, such as cirrhosis, end stage liver disease and hepatocellular carcinoma (HCC). HIV/HCV co-infection requires complex management, especially when HCC is present. Co-infected patients with HCC undergo the same therapeutic protocol as their mono-infected counterparts, but special issues such as interaction between regimens, withdrawal of therapy and choice of immunosuppressive agents, demand a careful approach by specialists. All these issues are analyzed in this minireview.
doi:10.4254/wjh.v5.i6.323
PMCID: PMC3692973  PMID: 23805356
Hepatocellular carcinoma; Hepatitis C virus, Human immunodeficiency virus; Co-infection
25.  Altered cytokine expression in T lymphocytes from human immunodeficiency virus Tat transgenic mice. 
Journal of Virology  1995;69(12):7622-7629.
Examination of the interaction between human immunodeficiency virus (HIV) regulatory gene products and the host immune system is fundamental to understanding the pathogenesis of HIV and could reveal possible targets for therapeutic intervention in the treatment of AIDS. The HIV Tat gene is a potential candidate for this type of strategy. Transgenic mice can be used to investigate the in vivo effects of Tat on the developing and dynamic immune system and on cellular gene expression. Thus, we have generated transgenic mice that harbor the HIV type 1 Tat gene under the transcriptional control of the human CD2 gene regulatory elements. This expression cassette results in high-level, tissue-specific transcription of the transgene within the T-cell compartment. In this report, we demonstrate the effects of Tat on the in vivo immune system. CD2-Tat transgenic mice show no signs of aberrant thymic development and have normal levels of T-cell subsets in the thymus and peripheral lymphoid organs. However, activated T cells from transgenic mice contain increased levels of tumor necrosis factor beta mRNA as well as biologically active tumor necrosis factor protein and express elevated levels of transforming growth factor beta and interleukin-4 receptor mRNA. These increased cytokine levels do not appear to alter mitogen- or antigen-stimulated responses or induce the formation of dermal lesions in ageing mice. Such investigations should provide insight into the combination of host immune factors mediating pathogenesis in HIV infection.
PMCID: PMC189702  PMID: 7494270

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