HIV diversity, recombination and disease progression: how does fitness "fit" into the puzzle?

HIV appears to have diverged into several lineages upon multiple zoonotic introductions from the nonhuman primates. The HIV-2 and HIV-1 groups M, N, and O likely represent different cross-species transmission events. The radial evolution of group M in multiple clades or subtypes is likely due to adaptation and expansions in the human hosts. It is not well understood why HIV strains such as HIV-1 subtype C in particular or group M in general have spread disproportionately as compared to other subtypes, groups, or types, which often remained geographically constrained to local epidemics. Host genetic effects, transmission bottlenecks, social/behavioral and environmental limitations, founder effect and other viral factors could have contributed to variable spread through the human population. Even after transmission, viruses evolve at different rates during disease progression. Recent studies have explored phenotypic differences between HIV types, groups, and subtypes in attempts to explain or understand this radial evolution and expansion. This review explores some of the important aspects relating to fitness during disease progression, during global distribution of different HIV subtypes, and related to circulation of recombinant forms in the epidemic.     

Plasma IP-10 Is Associated with Rapid Disease Progression in Early HIV-1 Infection

Abstract Cytokines play key roles in modulating disease progression in simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. There are a few studies on the relationship between early cytokines and HIV disease prognosis. In this study, we first report the relationship based on two groups with clearly different disease progression. We found that IP-10 was the only cytokine among the 26 cytokines tested that was always positively correlated with disease progression, and was associated with the time for CD4 counts to fall below 200 cells/μL during Fiebig stages III-V in HIV-1 infection. This suggests that high IP-10 levels in the blood are associated with rapid disease progression during Fiebig stages III-V in HIV-1 infection.     

High replication fitness and transmission efficiency of HIV-1 subtype C from India: Implications for subtype C predominance

HIV-1 subtype C has been the predominant subtype throughout the course of the HIV-1 epidemic in India regardless of the geographic region of the country. In an effort to understand the mechanism of subtype C predominance in this country, we have investigated the in vitro replication fitness and transmission efficiency of HIV-1 subtypes A and C from India. Using a dual infection growth competition assay, we found that primary HIV-1 subtype C isolates had higher overall relative fitness in PBMC than subtype A primary isolates. Moreover, in an ex vivo cervical tissue derived organ culture, subtype C isolates displayed higher transmission efficiency across cervical mucosa than subtype A isolates. We found that higher fitness of subtype C was not due to a trans effect exerted by subtype C infected PBMC. A half genome A/C recombinant clone in which the 3′ half of the viral genome of subtype A was replaced with the corresponding subtype C3′ half, had similar replicative fitness as the parental subtype A. These results suggest that the higher replication fitness and transmission efficiency of subtype C virus compared to subtype A virus from India is most probably not due to the envelope gene alone and may be due to genes present within the 5′ half of the viral genome or to a more complex interaction between the genes located within the two halves of the viral genome. These data provide a model to explain the asymmetric distribution of subtype C over other subtypes in India.     

HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV

It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a "genetic bottleneck", and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4(+) T cells express high levels of CCR5, and a subset of these CD4(+)/CCR5(high) cells express the integrin α?β?, the gut homing receptor. CD4(+)/CCR5(high)/ α4β7(high) T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α?β? on CD4(+) T cells. On CD4(+)/CCR5(high)/ α4β7(high) T cells, α?β? is closely associated with CD4 and CCR5. Furthermore, α?β? is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α?β? interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α?β? is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α?β? interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α?β? interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection.     

AIDS vaccines that allow HIV-1 to infect and escape immunologic control: a mathematic analysis of mass vaccination

Cytotoxic T lymphocyte (CTL)-based HIV vaccine concepts shown to reduce viremia and postpone disease but not to prevent infection in monkeys are currently in human phase 1 trials. To evaluate the potential efficacy of vaccines that cannot prevent HIV-1 to infect and escape immunologic control, we designed a mathematic model that correlates the level of viremia to both infectiousness and disease progression. We speculate that vaccinees will have a virologic set point and disease progression rates comparable to untreated HIV-1-infected individuals with the best prognosis. Our model (illustrated with R0 = 3) shows that a sexually active population can ultimately be reduced to 26% of its initial size as a result of AIDS-related mortality in the absence of treatment or vaccination. Start of vaccination when HIV-1 prevalence is still low might postpone the peak incidence of infection and the dramatic decline in population size by up to 22 years. In conclusion, CTL-based vaccines that do not prevent HIV-1 infection but do postpone the time to onset of AIDS have considerable potential to curb the spread of HIV-1 and to postpone high AIDS-related mortality on a population level. The number of long-term survivors is substantially increased only when vaccination is initiated early in an AIDS epidemic, however.     

Molecular and cellular interactions of HIV-1/HTLV coinfection and impact on AIDS progression

In the last 10 years HIV-1/human T-cell leukemia virus (HIV-1/HTLV) coinfection has emerged as a worldwide health problem. The numbers of HIV-1/HTLV-1 coinfections in South America and Africa are increasing, as well as HIV-1/HTLV-2 coinfections in the USA and Europe. Coinfections by either HTLV-1 or HTLV-2 and HIV-1 frequently occur in persons with a history of injection drug use. Since HTLV-1 preferentially infects CD4+ T-cells and HTLV-2 has a tropism for CD8+ T-cells, the influence of coinfection on HIV-1 disease progression may be different. The effect of HIV-1/HTLV-1 coinfection on HIV-I pathogenesis is controversial as soluble factors produced by HTLV-1 infected cells can either enhance or suppress HIV-1 infection. In HTLV-1/HIV-1 coinfected patients, upregulation of HIV-1 expression was attributed to strong activation of cytokines that promoted HIV infection. The introduction of HAART has dramatically reduced HIV-1 morbidity and mortality, but has given rise to an increased number of inflammatory syndromes. While HAART is successful for controlling HIV disease, it has little impact on HTLV-1/2 genome expression. The consequence of coinfection, even with HAART, may well be the reported increase in neurologic disease. Several epidemiologic and in vitro studies of the influence of HTLV infection on HIV-1 related AIDS progression suggest that HTLV-1 infection can promote HIV-1 replication and accelerate the clinical progression to AIDS. However, other studies have not confirmed these observations. The differences in study outcomes could be related to the occurrence of different HIV-1 phenotypes in clinical disease. In contrast, evidence points to a confirmed protective role of HTLV-2 that is manifested as improved survival and delayed progression to AIDS. The protective effect may be the result of maintaining normal-range levels of CD4 and CD8 counts, lowering HIV replication, and immune activation. As a corollary, the number of long-term nonprogressors for AIDS in the HIV-1/HTLV-2 coinfected group was found to be significantly higher than in HIV-1 monoinfected cases. Investigations of the natural factors induced by HTLV-2 that influence HIV-1 replication show that CCL3L1 (an isoform of CCL3) is preferentially induced in HTLV-2 exposed seronegative HIV individuals and in long-term nonprogressor HTLV-2/HIV-1 coinfected persons. The CCL3L 1 inhibits HIV replication and thus acts as a potent effector against both HIV infection and disease progression. As a complement to upregulation of CCL3L1, other chemokines and cytokines induced by HTLV-2 may contribute to induction of the Th1 response against invading pathogens, in contrast to the dominant Th2 response that appears to favor HIV infection. The number of individuals with either single HIV-1 or HTLV-2 infection, in a cohort of Italian intravenous drug users monitored for 20 years, decreased significantly over time. However, the magnitude of HTLV-2 decrease was significantly less than that of HIV-1, pointing to the need for increased attention to, and control of, HTLV infection. In conclusion, the long-term effects of HIV and HTLV coinfections are poorly understood and the mechanisms of dysregulation of cellular biosynthesis by HTLV that impact HIV disease progression remain elusive.     

人类免疫缺陷病毒感染细胞毒性T细胞逃逸突变的研究进展

人类免疫缺陷病毒（HIV）-1感染者体内活化的细胞毒性T细胞（CTL）反应不足以清除病毒，这是由于HIV。1在HLA限制的CTL压力下经常发生逃逸突变。但是，部分CTL逃逸突变会造成HIV病毒适应性的下降。近年来，人们对HIV-1感染中CTL逃逸突变的特征以及不同位点的逃逸突变在疾病进程中的作用进行了比较深入的研究，因而探讨CTL压力下HIV逃逸突变的规律有助于了解HIV-1自然感染中的免疫保护机制，并为开发有效的HIV疫苗提供依据。     

人类免疫缺陷病毒感染细胞毒性T细胞逃逸突变的研究进展

人类免疫缺陷病毒(HIV)-1感染者体内活化的细胞毒性T细胞(CTL)反应不足以清除病毒,这是由于HIV-1在HLA限制的CTL压力下经常发生逃逸突变.但是,部分CTL逃逸突变会造成HIV病毒适应性的下降.近年来,人们对HIV-1感染中CTL逃逸突变的特征以及不同位点的逃逸突变在疾病进程中的作用进行了比较深入的研究,因而探讨CTL压力下HIV逃逸突变的规律有助于了解HIV-1自然感染中的免疫保护机制,并为开发有效的HIV疫苗提供依据.     

人类免疫缺陷病毒感染细胞毒性T细胞逃逸突变的研究进展

人类免疫缺陷病毒(HIV)-1感染者体内活化的细胞毒性T细胞(CTL)反应不足以清除病毒,这是由于HIV-1在HLA限制的CTL压力下经常发生逃逸突变.但是,部分CTL逃逸突变会造成HIV病毒适应性的下降.近年来,人们对HIV-1感染中CTL逃逸突变的特征以及不同位点的逃逸突变在疾病进程中的作用进行了比较深入的研究,因而探讨CTL压力下HIV逃逸突变的规律有助于了解HIV-1自然感染中的免疫保护机制,并为开发有效的HIV疫苗提供依据.     

Absence of coreceptor switch with disease progression in human immunodeficiency virus infections in India

The envelope glycoprotein of the human immunodeficiency virus (HIV) utilizes CD4 as a receptor and CCR5 and/or CXCR4 as coreceptor to gain entry into the cell. The CCR5-tropic viruses, observed early in infection, could be important in transmission and the CXCR4-tropic viruses, observed late, may play an important role in disease progression. Viruses from 40 HIV-positive, asymptomatic or symptomatic individuals in India were isolated. Of 40 isolates 39 used CCR5. Thirty-three isolates were subtype C, 3 isolates were subtype A, and 4 isolates were HIV-2. Only 1 HIV-2 isolate, from a symptomatic individual, was dualtropic. Therefore, a majority of isolates from India belonged to subtype C and all the isolates utilized CCR5 exclusively irrespective of HIV disease status.     

Use of a novel GFP reporter cell line to examine replication capacity of CXCR4- and CCR5-tropic HIV-1 by flow cytometry

The rate of HIV-1 disease progression correlates strongly with plasma viral load and is likely to be influenced by both host and viral determinants. Though interest in the impact of viral replication capacity during HIV-1 infection has been increasing, especially with respect to drug resistance mutations, its influence on disease course remains poorly understood. This is due in part to significant drawbacks in conventional means of measuring HIV-1 growth in vitro (i.e. expense, inconvenience, and experimental variability). A FACS-based method is described here to measure HIV-1 replication sensitively and a modification of this method can be used to determine viral titer accurately. Importantly, the target cells used are permissive to CXCR4- and CCR5-tropic HIV-1 strains. In pilot experiments, the growth kinetics of laboratory-adapted strains NL4-3 and IIIB were examined carefully. Using this method, differences were observed in growth kinetics between three laboratory strains and seven primary isolates, indicating the potential for a broad range of in vitro replication capacities among individual isolates. In conclusion, this FACS-based method provides a sensitive approach to measure the replication capacity of HIV-1 and may prove useful in studies examining the impact of viral fitness on disease progression.     

Virologic testing in the management of perinatal HIV exposure

Over the last several years, virologic assays for the detection and measurement of HIV-1 RNA have become important in the diagnosis and management of perinatal HIV infection. Since AIDS Clinical Trials Group 076, a number of prospective and retrospective analyses have investigated the role of viral load in perinatal transmission. Although no universal virologic threshold for perinatal HIV transmission has been established, much has been learned about the timing of perinatal transmission and the relationship between maternal viral load and disease progression in HIV-infected neonates. Virologic assays have become accepted as standards of care in monitoring viral load during pregnancy, diagnosing neonatal infection, and establishing prognosis and response to therapy in infected infants.     

The role of anti-HSV therapeutics in the HIV-infected host and in controlling the HIV epidemic

The management of genital herpes in patients co-infected with human immunodeficiency virus (HIV) varies considerably from those without HIV infection. The International Herpes Management Forum (IHMF) has published guidelines for the diagnosis and management of herpes simplex virus (HSV) infection in the HIV-infected host. In 2004, these recommendations were supplemented after consideration of the most recent research conducted in this field, which adds to the growing body of evidence linking the epidemics of HSV-2 and HIV-1 infection. This article presents the supporting evidence for these recommendations and statements. Recent studies suggest that HSV-2 infection may elevate viral load during HIV-1 infection and hence lead to accelerated disease progression. It therefore seems logical to offer suppressive antiviral therapy routinely to HIV-positive patients. This approach is supported by studies demonstrating the safety and efficacy of HSV antiviral therapy in individuals co-infected with HSV and HIV. The question remains whether HSV antiviral therapeutics reduce the risk of HIV acquisition and transmission. Clinical trials are being conducted to address this question. HSV type-specific serological testing is warranted in those who are infected with, or who are at high risk of acquiring, HIV infection. However, in developing countries and resource-poor settings, their utility is less clear for a number of reasons. These aspects are also discussed.     

AIDS in Africa: A bioanthropological perspective

The epidemiological characteristics of acquired immunodeficiency syndrome (AIDS) in Africa are reviewed. Infection rates with human immunodeficiency virus 1 (HIV-1) and human immunodeficiency virus 2 (HIV-2) vary across the continent of Africa with the highest infection rates occurring in East and Central Africa. The primary pattern of infection with HIV-1 is characterized by high rates of heterosexual vs. homosexual transmission, a low male to female sex ratio of cases, and high rates of pediatric AIDS. Cultural anthropologists have emphasized variation in human sexual behavior as an important factor in understanding the HIV epidemic. These studies have focussed on understanding the range of sexual risk behaviors present in different cultures and the cultural meanings of these behaviors. Biological anthropologists approach the study of human disease with an interest in human biological variation, evolutionary models, and the interface between biology and behavior. A Bioanthropology Research Agenda for AIDS is proposed which focuses on these three areas. Potential research domains for biological anthropologists include: human biological variation and cofactors of infection and disease, the evolutionary impact of HIV infection, and the interface between biology and behavior and the biological impact of behavior. Working with colleagues in other disciplines, biological anthropologists can assist in furthering understanding of the variables of HIV infection and disease.     

Hitting HIV where it hurts: an alternative approach to HIV vaccine design

The ability of HIV-1 to mutate represents a major challenge to current vaccine approaches. However, some individuals achieving control of HIV during natural infection seem unique in their dominant targeting by cellular immune responses of conserved regions of HIV that, if mutated, exact a substantial impact on viral replicative capacity, or fitness. Notably, the partial suppression of HIV in treated individuals harboring viruses with drug-resistant mutations has also been linked to impaired viral fitness. The convergence of these observations suggests that vaccines designed to focus immune responses narrowly against regions of HIV susceptible to highly deleterious mutations might prove effective in controlling viral replication to levels that slow disease progression and reduce transmission. Therefore, it will be crucial to identify these "Achilles heels" of HIV that might represent uniquely susceptible targets, and test whether vaccine constructs enabling specific targeting of CD8(+) T-cell responses against such regions would enable the control of HIV and SIV.     

Coinfecting viruses as determinants of HIV disease

The human body constitutes a balanced ecosystem of its own cells together with various microbes (“host-microbe ecosystem”). The transmission of HIV-1 and the progression of HIV disease in such an ecosystem are accompanied by de novo infection by other microbes or by activation of microbes that were present in the host in homeostatic equilibrium before HIV-1 infection. In recent years, data have accumulated on the interactions of these coinfecting microbes—viruses in particular—with HIV. Coinfecting viruses generate negative and positive signals that suppress or upregulate HIV-1. We suggest that the signals generated by these viruses may largely affect HIV transmission, pathogenesis, and evolution. The study of the mechanisms of HIV interaction with coinfecting viruses may indicate strategies to suppress positive signals, enhance negative signals, and lead to the development of new and original anti-HIV therapies.     

Virological,immunological and host factors in HIV-1 discordant couples in Thailand

The potential factors of resistance to HIV-1 infection were investigated in 23 HIV discordantly infected couples, of each, one partner had HIV infection and the matched spouse was not infected. Both partners of the HIV discordant couples possessed comparable number of CD4+ cells expressing CCR5. Our study demonstrated that resistance to HIV-1 infection was not due to low level of HIV viral load in their infected-matched spouses. In addition, selective biological phenotype of HIV clinical isolates, which is indicative for risk of transmission, could not be determined in this study. However, we have demonstrated that the unknown genetic factor(s), and neutralizing antibody of broad and high activity could be taken into an account for resistance to HIV infection in the HIV discordant couples.     

Considering genetic profiles in functional studies of immune responsiveness to HIV-1

Over the last two decades HIV-1 has spread worldwide and has now surpassed malaria as the leading cause of infectious disease mortality in adults (http://www.who.int/infectious-disease-report/pages/ch1text.html). The clinical course and outcome of HIV-1 infection are highly variable among individuals. Most individuals infected with HIV develop AIDS within 10 years. However about 1-5% remain relatively healthy for 15 years or more (long-term nonprogressors), while others progress to AIDS within the first 2-3 years after infection (rapid progressors). A small number of individuals are resistant to infection, while some individuals appear to eliminate the virus. Factors that influence susceptibility to infection and rate of disease progression are a combination of viral, host, and environmental determinants. With few exceptions, genetic resistance to infectious diseases is likely to involve a complex array of host genetic effects involving variants that have very subtle, but significant consequences on gene expression or protein function. We have gained considerable insight into the genetic effects on HIV-1 disease, yet we likely have uncovered only a fraction of the total picture. The greater our knowledge of various effects on HIV disease, the more likely we will be able to predict disease outcome on an individual-by-individual basis. While this may seem obvious, there is no standard practice of taking into account the genetic profile (i.e. genotypes at loci known to associate with rate of AIDS progression) of subjects used in functional studies of immune responsiveness to HIV-1. Here, we propose an approach for assessing overall genetic risk on an individual basis, and suggest that this information be considered when selecting comparison groups in studies of immune responses to HIV and/or in the interpretation of data derived from such studies.