Basics of the virology of HIV-1 and its replication

Human immunodeficiency virus is undoubtedly the causative agent of AIDS. The understanding of HIV-1 pathogenesis is essentiell to develop and maintain antiretroviral treatment and vaccination. Since the first isolation of HIV-1 in cell culture, thousands of publications dealing with HIV and/or AIDS per year were released. In this review we give a basic overview of the virology of HIV-1 including the functions of the different HIV-1 proteins required for effective viral replication. Moreover, we summarize the interactive processes between HIV-1 and its target cells. Finally, the HIV-1 specific immune response and the current status of antiretroviral therapy are briefly described in this review.     

CD8+T-cell-mediated control of HIV-1 and SIV infection

A detailed understanding of the cellular response to human immunodeficiency virus (HIV-1) infection is needed to inform prevention and therapeutic strategies that aim to contain the AIDS pandemic. The cellular immune response plays a critical role in reducing viral load in HIV-1 infection and in the nonhuman primate model of SIV infection. Much of this virus suppressive activity has been ascribed to CD8(+)T-cell-directed cytolysis of infected CD4(+)T cells. However, emerging evidence suggests that CD8(+)T cells can maintain a lowered viral burden through multiple mechanisms. A thorough understanding of the CD8(+)T-cell functions in HIV-1 infection that correlate with viral control, the populations responsible for these functions, and the elicitation and maintenance of these responses can provide guidance for vaccine design and potentially the development of new classes of antiretroviral therapies. In this review, we discuss the CD8(+)T-cell correlates of protection in HIV-1 and SIV infection and recent advances in this field.     

Potential impact of antiretroviral therapy on HIV-1 transmission and AIDS mortality in resource-limited settings

OBJECTIVE: To estimate the potential impact of antiretroviral therapy on the heterosexual spread of HIV-1 infection and AIDS mortality in resource-limited settings. METHODS: A mathematic model of HIV-1 disease progression and transmission was used to assess epidemiologic outcomes under different scenarios of antiretroviral therapy, including implementation of World Health Organization guidelines. RESULTS: Implementing antiretroviral therapy at 5% HIV-1 prevalence and administering it to 100% of AIDS cases are predicted to decrease new HIV-1 infections and cumulative deaths from AIDS after 10 years by 11.2% (inter-quartile range [IQR]: 1.8%-21.4%) and 33.4% (IQR: 26%-42.8%), respectively. Later implementation of therapy at endemic equilibrium (40% prevalence) is predicted to be less effective, decreasing new HIV-1 infections and cumulative deaths from AIDS by 10.5% (IQR: 2.6%-19.3%) and 27.6% (IQR: 20.8%-36.8%), respectively. Therapy is predicted to benefit the infected individual and the uninfected community by decreasing transmission and AIDS deaths. The community benefit is greater than the individual benefit after 25 years of treatment and increases with the proportion of AIDS cases treated. CONCLUSIONS: Antiretroviral therapy is predicted to have individual and public health benefits that increase with time and the proportion of infected persons treated. The impact of therapy is greater when introduced earlier in an epidemic, but the benefit can be lost by residual infectivity or disease progression on treatment and by sexual disinhibition of the general population.     

HIV controllers: how do they tame the virus?

HIV controllers are rare, chronically HIV-1-infected patients in whom viral replication is undetectable in the absence of antiretroviral treatment. Most such patients are nonetheless infected by replication-competent viruses. An effective, multifunctional HIV-specific CD8(+) T-cell response is thought to be central to viral control in these individuals. The mechanisms underlying this spontaneous control of HIV infection and the particular characteristics of the CD8(+) T-cell response in HIV controllers are the focus of intensive investigations, because they should help to unravel the pathogenesis of AIDS and to provide new clues for the design of effective vaccine strategies. In this review, we examine recent findings from these studies.     

Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United StatesRevised November 3, 2000

Abstract

These recommendations update the February 25, 2000 guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission.* This report provides health-care providers with information for discussion with HIV-1 infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy and use of elective cesarean delivery to reduce perinatal HIV-1 transmission. Various circumstances that commonly occur in clinical practice are presented as scenarios and the factors influencing treatment considerations are highlighted in this report. It is recognized that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving. The Perinatal HIV Guidelines Working Group will review new data on an ongoing basis and provide regular updates to the guidelines; the most recent information is available on the HIV/AIDS Treatment Information Service (ATIS) website (http://www.hivatis.org).

In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1 infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy, pregnancy is not a reason to defer standard therapy. The use of antiretroviral drugs in pregnancy requires unique considerations, including the potential need to alter dosing as a result of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily to treat HIV-1 infection, to reduce perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy for infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen.     

Antiretroviral prophylaxis of perinatal HIV-1 transmission and the potential impact of antiretroviral resistance

Since 1994, trials of zidovudine, zidovudine and lamivudine, and nevirapine have demonstrated that these antiretroviral drugs can substantially reduce the risk of perinatal HIV-1 transmission. With reductions in drug price, identification of simple, effective antiretroviral regimens to prevent perinatal HIV-1 transmission, and an increasing international commitment to support health care infrastructure, antiretrovirals for both perinatal HIV-1 prevention and HIV-1 treatment will likely become more widely available to HIV-1-infected persons in resource-limited countries.In the United States, widespread antiretroviral usage has been associated with increased antiretroviral drug resistance. This raises concern that drug resistance may reduce the effectiveness of perinatal antiretroviral prophylaxis as well as therapeutic intervention strategies. The purpose of this article is to review what is known about resistance and risk of perinatal HIV transmission, assess the interaction between antiretroviral resistance and the prevention of perinatal HIV-1 transmission, and discuss implications for current global prevention and treatment strategies.     

US Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States,February 25, 2000, by the Perinatal

Abstract

These recommendations update the 1994 guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report provides health care providers with information for discussion with HIV-1 infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy. Various circumstances that commonly occur in clinical practice are presented as scenarios and the factors influencing treatment considerations are highlighted in this report. It is recognized that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving. The Perinatal HIV Guidelines Working Group will review new data on an ongoing basis and provide regular updates to the guidelines; the most recent information is available on the HIV/AIDS Treatment Information Service (ATIS) website (http://www.hivatis.org).

In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1-infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy, pregnancy is not a reason to defer standard therapy. The use of antiretroviral drugs in pregnancy requires unique considerations, including the potential need to alter dosing as a result of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily to treat HIV-1 infection, to reduce perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy for infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen. Information included in these guidelines may not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. Specifically, the terms “safe” and “effective” may not be synonymous with the FDA-defined legal standards for product approval.     

Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus

The availability of highly active antiretroviral therapies (HAART) has not eliminated HIV-1 infection of the central nervous system (CNS) or the occurrence of HIV-associated neurological problems. Thus, the neurobiology of HIV-1 is still an important issue. Here, we review key features of HIV-1-cell interactions in the CNS and their contributions to persistence and pathogenicity of HIV-1 in the CNS. HIV-1 invades the brain very soon after systemic infection. Various mechanisms have been proposed for HIV-1 entry into the CNS. The most favored hypothesis is the migration of infected cells across the blood-brain barrier ("Trojan horse" hypothesis). Virus production in the CNS is not apparent before the onset of AIDS, indicating that HIV-1 replication in the CNS is successfully controlled in pre-AIDS. Brain macrophages and microglia cells are the chief producers of HIV-1 in brains of individuals with AIDS. HIV-1 enters these cells by the CD4 receptor and mainly the CCR5 coreceptor. Various in vivo and cell culture studies indicate that cells of neuroectodermal origin, particularly astrocytes, may also be infected by HIV-1. These cells restrict virus production and serve as reservoirs for HIV-1. A limited number of studies suggest restricted infection of oligodendrocytes and neurons, although infection of these cells is still controversial. Entry of HIV-1 into neuroectodermal cells is independent of the CD4 receptor, and a number of different cell-surface molecules have been implicated as alternate receptors of HIV-1. HIV-1-associated injury of the CNS is believed to be caused by numerous soluble factors released by glial cells as a consequence of HIV-1 infection. These include both viral and cellular factors. Some of these factors can directly induce neuronal injury and death by interacting with receptors on neuronal membranes (neurotoxic factors). Others can activate uninfected cells to produce inflammatory and neurotoxic factors and/or promote infiltration of monocytes and T-lymphocytes, thus amplifying the deleterious effects of HIV-1 infection. CNS responses to HIV-1 infection also include mechanisms that enhance neuronal survival and strengthen crucial neuronal support functions. Future challenges will be to develop strategies to prevent HIV-1 spread in the brain, bolster intrinsic defense mechanisms of the brain and to elucidate the impact of long-term persistence of HIV-1 on CNS functions in individuals without AIDS.     

Course of viral load throughout HIV-1 infection

HIV-1 RNA levels are routinely monitored as part of patient management. However, little is known about the course of HIV-1 RNA levels over the entire period of infection. The aim of this study was to investigate the course of HIV-1 RNA levels in a cohort of men with hemophilia who were observed for up to 17 years after HIV-1 seroconversion, and to assess the risk of HIV disease progression at any HIV-1 RNA level. Viral loads were measured on annual stored serum samples in 107 men with hemophilia A using the Roche Amplicor Monitor assay with non-B primers. On average, HIV-1 RNA levels increased significantly by 0.11 log10 per year over the course of HIV infection. This rate of increase was significantly faster in those who developed AIDS or died over the subsequent 12 to 17 year period, and in those who were older at HIV- 1 seroconversion. The risk of developing AIDS and death remained low when the HIV-1 RNA level was below 4 log10 copies/ml, but increased rapidly thereafter, supporting current guidelines for the initiation of antiretroviral therapy after the viral load has exceeded this level.     

Surrogate markers for disease progression in treated HIV infection.

OBJECTIVE: To characterize the relationships among highly active antiretroviral therapy (HAART), HIV-1 RNA levels, immune system markers, and clinical outcome in a cohort of HIV-1-infected homosexual men. PATIENTS: A total of 123 men enrolled in the Amsterdam cohort study of HIV-1 infection and AIDS with a documented seroconversion for HIV-1 antibodies and known date of seroconversion were included in this study. METHODS: CD4 + /CD8 + T-cell counts and HIV-1 RNA levels in plasma were measured approximately every 6 months. Dates of starting and stopping antiretroviral therapy were also recorded. The relationship between HIV-1 RNA in plasma, CD4 + /CD8 + T-cell counts and HAART and their influence on clinical outcome were examined using a graphical chain modeling approach. Generalized estimating equations were used to examine correlations among the three disease markers. Hazards models with time-dependent covariates were used to examine the influence of HAART and the disease markers on progression to AIDS. RESULTS: HAART was significantly associated with reduced disease progression (relative hazard [RH] of AIDS, 0.20;, 95% confidence interval [CI], 0.05-0.85). The most recent HIV-1 RNA measurement and CD4 + T-cell count are independently associated with disease progression (adjusted RH for HIV-1 RNA 1.8 per log 10 increase; 95% CI, 1.2-2.6, p =.002; adjusted RH for CD4 + 0.48 per 100 x 10(6)/L increase; 95% CI, 0.40-0.58; p <.001). Depending on these measurements, HAART was no longer significantly associated with AIDS (adjusted RH, 0.81; 95% CI, 0.18-3.6; p =.78). CONCLUSIONS: HIV-1 RNA levels in plasma and CD4 + T-cell counts are currently considered as effective surrogate markers for the effect of HAART on disease progression in this cohort.     

HAART is neuroprophylactic in HIV-1 infection

BACKGROUND: To find out about the prophylactic value of antiretroviral therapy on HIV-1-associated subclinical and clinical psychomotor slowing as one marker of HIV-1-associated CNS disease. METHODS: Prospective study with regular clinical and neurophysiologic examination every three months of 1482 consecutive HIV-1-seropositive and AIDS patients seen at our department till June 30, 1999. RESULTS: Antiretroviral therapy has a significant prophylactic value over an individual observation period of ten years with regard to the first, potentially transient manifestation of HIV-1-associated subclinical psychomotor slowing and with regard to the clinical manifestation of motor signs. However, a subgroup of patients is characterized through a second, more sustained manifestation of subclinical psychomotor slowing which cannot be prevented by any type of currently available antiretroviral therapy. CONCLUSIONS: These findings suggest the existence of different pathomechanisms underlying HIV-1-associated brain disease which may in part be effectively prevented, but which in part also escape all antiretroviral treatment strategies in use today.     

Underlying mechanisms of HIV-1 latency

Similarly to other retroviruses, HIV-1 integrates its genome into the cellular chromosome. Expression of viral genes from the integrated viral DNA could then be regulated by the host genome. If the infected cell suppresses viral gene expression, the virus will undergo latency. The latently infected cells cannot be detected or cleared by the immune system since they do not express viral antigens. These cells remain undetected for several years, even under antiretroviral treatments. The silenced HIV-1 DNA could be reactivated under certain conditions. Despite the efficient use of antiretroviral drugs, HIV-1 latently infected cells remain the major obstacles to a permanent cure. In this review, we discuss the cellular and molecular mechanisms through which HIV-1 establishes latency.     

Immunomodulatory Effects of Intravenous Immunoglobulins (IVIGs) in HIV-1 Disease: A Systematic Review

Intravenous immunoglobulins (IVIGs) are generally used as replacement therapy for humoral immunodeficiencies. In consideration of their immune-modulating properties, they are also employed as “immune-modulating/anti-inflammatory” treatment in different clinical conditions. In HIV-1 infection, an increased incidence of autoimmune and auto-inflammatory manifestations has been described, probably as a consequence of the chronic immune activation associated with the disease. The initial use in the treatment of bacterial infections in children with HIV/AIDS has been replaced by the treatment, in combination with antiretroviral therapy, of these autoimmune/inflammatory conditions. We review the results obtained with IVIGs therapy in these HIV-1-associated clinical manifestations.     

Immunomodulatory effects of intravenous immunoglobulins (IVIGs) in HIV-1 disease: a systematic review

Intravenous immunoglobulins (IVIGs) are generally used as replacement therapy for humoral immunodeficiencies. In consideration of their immune-modulating properties, they are also employed as "immune-modulating/anti-inflammatory" treatment in different clinical conditions. In HIV-1 infection, an increased incidence of autoimmune and auto-inflammatory manifestations has been described, probably as a consequence of the chronic immune activation associated with the disease. The initial use in the treatment of bacterial infections in children with HIV/AIDS has been replaced by the treatment, in combination with antiretroviral therapy, of these autoimmune/inflammatory conditions. We review the results obtained with IVIGs therapy in these HIV-1-associated clinical manifestations.     

Vector replication and expression of HIV-1 antigens by the HIV/AIDS vaccine candidate MVA-B is not affected by HIV-1 protease inhibitors

MVA-B is an attenuated poxvirus vector expressing human immunodeficiency virus type 1 Env, Gag, Pol, and Nef antigens from clade B, and is considered a promising HIV/AIDS vaccine candidate. Recently, a phase I clinical trial in human healthy volunteers has shown that MVA-B is safe and highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4(+) and CD8(+) T cell responses to HIV-1 antigens, with preference for effector memory T cells; and it also triggers the induction of specific antibodies to Env in most of the vaccines. While MVA recombinants expressing HIV-1 antigens are being used or plan to use in therapeutic clinical trials, little is known on the effect of HIV-1 highly active antiretroviral therapy in MVA life cycle. To define this role, here we have evaluated in established cell cultures and human dendritic cells to what extent different HIV-1 protease inhibitors affect virus replication and expression of HIV-1 antigens during MVA-B infection. The results obtained revealed that the most commonly used HIV-1 protease inhibitors (atazanavir, ritonavir, and lopinavir) had no effect on MVA-B virus growth kinetics, even at higher concentrations than those normally used on HAART. Furthermore, expression of gp120 and the fused Gag-Pol-Nef polyprotein in permissive and non-permissive cells infected with MVA-B were also not affected. These findings are relevant information for the therapeutic use of MVA-B as an HIV-1/AIDS vaccine.     

Antiretroviral therapy is associated with an atherogenic lipoprotein phenotype among HIV-1-infected men in the Multicenter AIDS Cohort Study

BACKGROUND: Alterations in serum lipids and an increased risk of myocardial infarction have been associated with HIV-1 infection and its treatment. METHODS: Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy in frozen plasma samples from participants in the Multicenter AIDS Cohort Study. The effects of HIV-1 infection, antiretroviral therapy, and other factors on median particle concentrations were examined using quantile regression. RESULTS: Fasted samples were tested from 1082 men, including 609 HIV-seronegative and 473 HIV-1-infected men. Compared with HIV-seronegative men, HIV-1-infected men on antiretroviral therapy had an atherogenic phenotype with higher numbers of very low density lipoprotein and small low-density lipoprotein particles and lower numbers of high-density lipoprotein and large low-density lipoprotein particles. HIV-infected, antiretroviral-naive men had significantly lower high-density lipoprotein and small low-density lipoprotein particle concentrations compared with the HIV-seronegative men. Among men on antiretroviral therapy, the atherogenic phenotype was most pronounced in men with a good clinical status. CONCLUSION: Use of antiretroviral therapy in HIV-1-infected men was associated with an "atherogenic lipoprotein phenotype."     

Impact of HIV-1 infection on the feto-maternal crosstalk and consequences for pregnancy outcome and infant health

Adaptation of the maternal immune system to establish maternal/fetal equilibrium is required for a successful pregnancy. Viral infections, including HIV-1 infection, can alter this maternal/fetal equilibrium, with significant consequences for pregnancy outcome, including miscarriages, impaired fetal growth, and premature delivery. Furthermore, maternal HIV-1 infection has been shown to have a long-term impact on the developing fetal immune system also when the infant is not infected with the virus. In this review, we discuss the consequences of maternal HIV-1 infection and antiretroviral therapy on pregnancy outcome and the health of the uninfected HIV-1-exposed infant.     

蛋白质翻译后修饰调控HIV-1潜伏感染

艾滋病是一种由人类免疫缺陷病毒 （HIV） 引起的获得性免疫缺陷综合征。HIV 可分为 HIV-1 型和 HIV-2 型。 HIV-1全球流行,造成严重的危害。尽管抗逆转录病毒联合疗法 （cART） 的应用可以延长患者寿命,但HIV-1感染目前仍然不能完全治愈。HIV-1感染治愈最主要的障碍就是病毒潜伏库的存在。HIV-1潜伏库可以被定义为一群携带具备复制潜力的 HIV-1前病毒的长寿命静息 CD4⁺ T 细胞。蛋白质翻译后修饰使得病毒蛋白和宿主细胞蛋白形成了更复杂的相互作用网络。 HIV-1潜伏库的形成与调控,也与病毒和宿主蛋白的翻译后修饰密切相关。因此,本文将从病毒蛋白和宿主蛋白翻译后修饰的角度阐述HIV-1潜伏的建立与调控的机制。这将有助于HIV-1治疗新靶点的探索和研发,并有利于实现HIV-1感染的功能性治愈目标。最后,本文还会综述有关以蛋白质翻译后修饰为靶点的HIV-1药物研究进展,为后续HIV-1治疗药物的研发提供思路和启发。     

Plasma HIV-1 RNA to guide patient selection for antiretroviral therapy in resource-poor settings: efficiency related to active case finding

Scaling up access to highly active antiretroviral therapy (HAART) requires eligibility criteria that safeguard treatment efficiency in resource-poor settings. We determined whether supply of HAART on the basis of plasma viral load testing could result in a stronger reduction of AIDS incidence as compared with CD4 count-driven strategies. Expected AIDS incidence rates corresponding to distinct HAART eligibility criteria were calculated by relying on risk parameters obtained through the Amsterdam cohort studies on HIV infection and AIDS. We modeled 2 different treatment settings derived from sub-Saharan African surveys. In a hospital-based setting, the reduction in the 1-year AIDS incidence is the same for any HAART administration rate if patients are selected on a single CD4 cell count criterion or on (additional) criteria for plasma HIV-1 RNA. In a community-based setting, where patients are identified at less advanced stages of infection, the reduction in the 1-year AIDS incidence is higher at particular HAART administration rates if patients are selected on criteria for plasma HIV-1 RNA rather than CD4 cell count. Plasma viral load testing can ensure a more efficient allocation of antiretroviral therapy but only when applied to a strategy of active case finding in the community.     

Does genetic diversity of HIV-1 non-B subtypes differentially impact disease progression in treatment-naive HIV-1-infected individuals? A systematic review of evidence: 1996-2010

With 88% of HIV-1-infected individuals living in areas of high prevalence of non-B subtypes and with expanded global access to antiretroviral treatment (ART), studying disease progression amongst non-B subtypes gains relevance. Optimized clinical management is a possibility with knowledge of non-B subtype profiles at baseline, which is currently not possible due to lack of subtype-specific point-of-care assays. In a systematic review, we synthesized global evidence on differential disease progression amongst non-B subtypes in ART-naive individuals. Due to lack of consistent effect measures, we avoided pooling data and inferred patterns with respect to disease progression outcomes (ie, AIDS, Death, CD4, viral load changes). Subtypes C and D were more aggressive, followed by G, AE, and AG, and A being the least aggressive of all HIV-1 subtypes. Evidence of greater rates of disease progression in globally prevalent C and D subtypes highlight the importance of expanding early HIV detection, and determining subtype profile at baseline with CD4 staging to optimize the quality of ART delivery and care in global settings.