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PubMed1995

Nef and LTR sequence variation from sequentially derived human immunodeficiency virus type 1 isolates.

Variation in HIV-1 nef and LTR DNA sequences was assessed longitudinally during disease progression in four HIV-1-infected subjects. Point mutations were found among quasispecies obtained at a single time point in each individual, with increasing diversity with disease progression in two of three patients for whom sufficient data were available for analysis. Deletions and rearrangements were more common in late than early stages of disease. Continued sequence evolution in HIV-1 quasispecies with nef deletions along with coexistence of nef-bearing quasispecies suggest that nef-deleted quasispecies are capable of replication in vivo, possibly complemented by quasispecies lacking such deletions and/or by adaptation to a specialized niche within the patients.

Amino Acid Sequence↗

PubMed1994

Polio vaccines and the origin of AIDS.

Although mass vaccination programs have resulted in the eradication of a number of human infectious diseases, vaccine contamination has been a persistent concern. In particular, it is now known that the early polio vaccines were contaminated with at least one monkey virus, SV40. The transfer of monkey viruses to man via contaminated vaccines is particularly relevant to the acquired immunodeficiency syndrome (AIDS), since the causative agent of AIDS, human immunodeficiency virus (HIV), is thought to be derived from a simian precursor virus. Furthermore, human infection with this virus appears to be a relatively recent event. We hypothesize that the AIDS pandemic may have originated with a contaminated polio vaccine that was administered to inhabitants of Equatorial Africa from 1957 to 1959. The mechanism of evolution of HIV from this vaccine remains to be determined.

Accidents↗

PubMed1999

Determinants of the natural history of human immunodeficiency virus type 1 infection.

Variation in the time to AIDS and duration of survival of human immunodeficiency virus (HIV)-1-infected persons was recognized early in the epidemic. Recent studies have indicated that the rate of viral replication, as manifest by the number of copies of HIV RNA per milliliter of plasma, is a major determinant of outcome in an infected person. The predictive power of the measurement of plasma HIV RNA copy number is enhanced by combining this result with the CD4 lymphocyte number. The determinants of the rate of viral replication are less clearly defined. Recent studies suggest that polymorphism of the chemokine receptors, required for cellular infection, plays a role in regulating the rate of viral replication. The subsequent adaptive evolution of HIV-1 to the host's immune response is a consequence of this dynamic of the virus. Complicating opportunistic infections also appear to enhance HIV-1 replication, while antiviral therapy, in contrast, can and does suppress viral replication.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Rates and dates of divergence between AIDS virus nucleotide sequences.

The acquired immune deficiency syndrome (AIDS), caused by a retrovirus called human immunodeficiency virus (HIV), has become a pandemic. A knowledge of the rate of nucleotide substitution in HIV and of the history and pattern of spread of the virus is important for understanding the epidemiology and pathogenesis of AIDS and for developing therapies and vaccine strategies. A new model has been developed and used to estimate the substitution rates in various regions in the HIV genome. The rate of nonsynonymous (amino acid-changing) substitution is lowest in the regions coding for the capsid proteins and the reverse transcriptase, being approximately 1.7 X 10(-3) nucleotide substitutions/site/year. The nonsynonymous rate is extremely high (14 X 10(-3] in the hypervariable regions of the envelope gene, suggesting extremely rapid change in viral antigenicity. The nonsynonymous rates in the other coding regions are between 3 X 10(-3) and 7 X 10(-3). The average synonymous rate for the HIV genome is 10 X 10(-3). These rates are 10(6) times greater than the rates in DNA genomes and at least as high as the rates in other RNA viruses. Evidence is provided for a case of recombination between different HIV strains. Our analysis suggests that the AIDS virus had existed in central Africa before 1960 and spread to North America before the mid 1970s. The evolutionary relationships among HIV isolates are inferred from nucleotide sequence data, and the result is consistent with the view that AIDS spread from Haiti to the United States.

Base Sequence↗

PubMed1999

Functional complementation of the envelope hypervariable V3 loop of human immunodeficiency virus type 1 subtype B by the subtype E V3 loop.

The hypervariable V3 loop within gp120 of human immunodeficiency virus type 1 (HIV-1) is the major determinant of cell tropism and the entry coreceptor usage of the virus. However, the information obtained thus far has been from only subtype B from North America and Europe, and little is known about other subtypes whose V3 amino acids differ by as much as 50% from subtype B V3. In this study, we examined the functional potential of the V3 element of the HIV-1 subtype E, the most crucial variant causing the AIDS epidemic throughout southeast Asia. A panel of HIV-1LAI recombinants was constructed by the overlap extension method, by which the LAI V3 loop was precisely replaced by that of the subtype E nonsyncytium-inducing (NSI) or syncytium-inducing (SI) variant. All of the recombinant viruses infected peripheral blood mononuclear cells, whereas only those with SI V3 infected MT2 cells, a CD4(+) T cell line. Consistently, the SI V3 recombinants used CXCR4, while the NSI V3 recombinants used CCR5 for infection of HOS-CD4(+) cells. Finally, only the NSI V3 sequence conferred CC-chemokine sensitivity on the parental virus. The data support the notion that the HIV-1 V3 loop consists of a relatively independent domain in gp120 and suggest that the subtype E V3 loop indeed contains the functional element to dictate the cell tropism, coreceptor preference, and chemokine sensitivity of the virus. These findings are of immediate importance in understanding V3 structure-function relationship and for examining phenotypic evolution of HIV-1 subtype E.

Amino Acid Sequence↗

PubMed2004

Assessment of longitudinal changes in HIV-specific effector activity in subjects undergoing untreated primary HIV infection.

BACKGROUND: Despite the failure of HIV-specific cell-mediated immune responses to clear the virus, these cells play a critical role in the control of viral replication throughout HIV infection. OBJECTIVE: To characterize the natural evolution of the HIV-specific immune response in HIV primary infection (PI). METHODS: Untreated individuals, recruited in HIV PI, were monitored for the evolution of HIV-specific immune responses starting in early HIV disease. Longitudinal analysis of changes in the magnitude and breadth of HIV-specific responses to a panel of MHC class I-restricted peptides was performed using the quantitative interferon-gamma ELISPOT assay. RESULTS: Although immune responses were detected in all individuals at all times tested, the pattern of the immune responses differed significantly from that seen in subjects treated in PI. Untreated PI subjects exhibited dramatic changes with time in the frequency of individual HIV peptide-specific T-cell responses. In contrast HIV-specific immunity was stable in subjects treated in early PI or decreased in intensity and breadth in individuals treated later in PI. In untreated subjects the overall magnitude of HIV-specific reactivity persisted over at least 12 months whereas the number of peptides recognized declined. CONCLUSION: Given that a significant relationship existed between the magnitude of the HIV-specific response and viral load, it is likely that these effector cell expansions and contractions are driven by changes in antigen load.

Adolescent↗

PubMed1993

HTLV-II/HIV-1 coinfection and risk for progression to AIDS among intravenous drug users.

To determine whether coinfection with HTLV-II influences the course of HIV-1 infection, we evaluated the progression from asymptomatic HIV infection (CDC group II) to persistent generalized lymphadenopathy (CDC group III) to AIDS-related complex (CDC group IVA) to full-blown AIDS (CDC group IVC) to death from AIDS in two groups of HIV-seropositive intravenous drug users (IVDUs). The first group consisted of 123 patients infected with HIV-1 only, and the second comprised 22 patients with serological and molecular evidence of HTLV-II/HIV-1 coinfection. Results of the immunological and clinical follow-up indicated a greater likelihood of developing persistent generalized lymphadenopathy among individuals infected with HIV-1 alone than among those coinfected with HTLV-II. However, no statistical difference was detected between the two groups in the depletion of CD4+ cells, the temporal decrease of the CD4/CD8 ratio, or the progression to ARC or AIDS or to death from AIDS. These findings suggest that HTLV-II may have no effect on the clinical evolution of HIV infection in IVDUs, which may be explained by the lack of pathogenicity of the HTLV-II coinfecting strain(s) and/or other still unclear biological or immunological cofactors or mechanisms.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Passive sexual transmission of human immunodeficiency virus type 1 variants and adaptation in new hosts.

Human immunodeficiency virus type 1 (HIV-1) genetic diversity is a major obstacle for the design of a successful vaccine. Certain viral polymorphisms encode human leukocyte antigen (HLA)-associated immune escape, potentially overcoming limited vaccine protection. Although transmission of immune escape variants has been reported, the overall extent to which this phenomenon occurs in populations and the degree to which it contributes to HIV-1 viral evolution are unknown. Selection on the HIV-1 env gene at transmission favors neutralization-sensitive variants, but it is not known to what degree selection acts on the internal HIV-1 proteins to restrict or enhance the transmission of immune escape variants. Studies have suggested that HLA class I may determine susceptibility to HIV-1 infection, but a definitive role for HLA at transmission remains unproven. Comparing populations of acute seroconverters and chronically infected patients, we found no evidence of selection acting to restrict transmission of HIV-1 variants. We found that statistical associations previously reported in chronic infection between viral polymorphisms and HLA class I alleles are not present in acute infection, suggesting that the majority of viral polymorphisms in these patients are the result of transmission rather than de novo adaptation. Using four episodes of HIV-1 transmission in which the donors and recipients were both sampled very close to the time of infection we found that, despite a transmission bottleneck, genetic variants of HIV-1 infection are transmitted in a frequency-dependent manner. As HIV-1 infections are seeded by unique donor-adapted viral variants, each episode is a highly individual antigenic challenge. Host-specific, idiosyncratic HIV-1 antigenic diversity will seriously tax the efficacy of immunization based on consensus sequences.

AIDS Vaccines↗

PubMed1991

The natural history of HIV-1 infection: staging classifications of disease.

We evaluated and compared four staging classification systems for HIV infection in a population-based cohort: (1) a staging based on prodromal clinical criteria; (2) the Walter Reed Staging Classification (WRSC); (3) the immunologic staging system (ISS), and (4) a simple staging based on oral disease and CD4+ T-cell depletion. The staging systems were applied to 386 HIV-infected men in the San Francisco Men's Health Study cohort who did not have AIDS at the baseline examination. After 48-56 months of follow-up the cumulative incidence of AIDS and the cumulative mortality by stage was determined for each staging. Unlike the other systems, the WRSC could not classify a substantial proportion of HIV-infected men (51.9%). The WRSC and ISS include one or more stages which did not appear to be associated with a prognosis substantially different from that of adjacent stages. The simplified staging system based on CD4+ T-cell depletion and oral disease may be the most effective of the systems studied. A more complete understanding of the pathophysiology during the evolution of HIV infection will be required to define a more detailed staging of this disease.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

[Economic and socio-behavioural issues related to highly active antiretroviral therapies for HIV infection: the contribution of social science research].

This article presents a synthesis of the main topics covered by social science research (SSR) on HIV/AIDS, since the advent of highly active antiretroviral therapies (HAART) in 1996. SSR has shown that non-adherence cannot be reliably < > on the sole basis of a few a priori patient characteristics that clinicians could easily identify before initiation of HAART, and that a dynamic approach to adherence, continuously monitoring the impact of patients' subjective experience with HAART is needed. In relationship with the evolution of HIV infection toward a < >, SSR has dealt with the impact of HAART on all aspects of patients' daily lives (from employment and professional status to sexuality). It has also emphasised the potential contradictions between the hopes generated by these cost-effective therapeutic advances, on the one hand, and the high social vulnerability of a growing proportion of people living with HIV-AIDS, on the other hand. Finally, SSR suggests recommendations for < > AIDS public policies without losing the potential for innovations that the fight against this epidemic has introduced in health care and < > systems, as well as physician-patient's relationships.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Mannose-binding lectin gene polymorphism and its impact on human immunodeficiency virus 1 infection.

Mannose-binding lectin (MBL) is a serum protein whose low concentration is associated with the occurrence of allele variants named MBL*B, MBL*C and MBL*D. The present study investigated the association between MBL gene polymorphism and the susceptibility to HIV-1 infection. The study of 145 HIV-1-infected subjects and 99 healthy controls showed the presence of alleles MBL*A, MBL*B and MBL*D, whose frequencies were 69%, 22% and 09% among patients and 71%, 13% and 16% among healthy controls, respectively. The presence of the variant MBL*B was associated with higher plasma viral load levels, suggesting the importance of the MBL gene polymorphism in the clinical evolution of HIV-1-infected patients.

Alleles↗

PubMed2003

Is resistance futile?

A global effort has been undertaken to control human immunodeficiency virus (HIV) though the development of vaccines and pharmacologics. Current FDA approved pharmacological inhibitors target two of the three viral enzymes critical to replication and maturation of infectious viral particles: reverse transcriptase (RT) and protease (Pr). Although combination therapies targeting RT and Pr have significantly reduced AIDS related morbidity and mortality, resistance to individual inhibitors is a growing concern. Currently, there are six protease inhibitors in clinical use. These inhibitors target the active site of protease using peptidomimetic transition state analogs based on natural substrates. However, treatment failures arise as a lack of compliance due to HIV-inhibitor pharmacokinetics, toxicity, and tolerance. This allows reduced HIV-inhibitor pressure, increased viral replication, and the emergence of drug resistant mutations. Continued use of protease inhibitors in the face of incomplete viral suppression may result in HIV-1 escape mutants not only being resistant to the protease inhibitor used, but to all clinically available protease inhibitors. Thus, new broad-based protease inhibitors are needed to control the emerging multi-drug, cross-resistant HIV-1. Moreover, given the emergence of cross-resistant HIV-1, there is a need to target novel protease structural sites to reduce the risk of multi-drug cross-resistance. In this review, we discuss the resistance to protease inhibitors and the rationale for new strategies towards drug design for suppressing protease activity. We focus on the structure and function relationship and the influence that drug resistance mutants exert on the evolution of HIV-1 protease.

Amino Acid Sequence↗

PubMed1993

In vitro evolution of functional nucleic acids: high-affinity RNA ligands of HIV-1 proteins.

SELEX (Systematic Evolution of Ligands by EXponential enrichment) is a protocol for isolating, from a pool of variant nucleic acid sequences, high-affinity ligands to a target protein [Tuerk and Gold, Science 249 (1990) 505-510]. This procedure involves cycles of affinity selection by a target molecule from a heterogeneous population of nucleic acids, replication of the bound species (the ligands), and in vitro transcription to generate an enriched pool of RNA. We have used the SELEX procedure to obtain high-affinity RNA ligands against the reverse transcriptase and the Rev and Tat proteins of human immunodeficiency virus 1 (HIV-1). Through sequence comparisons within the collection of ligands isolated for each of these target proteins, we derive consensus descriptions of what secondary structure and primary sequences are required for binding. These descriptions serve as the starting point for the ultimate development of compounds intended to alter the course of HIV-1 infection.

Base Sequence↗

PubMed2004

Purifying selection masks the mutational flexibility of HIV-1 reverse transcriptase.

DNA and RNA polymerases share a core architecture composed of three structurally conserved motifs: A, B, and C. Although the amino acid sequences of these motifs are highly conserved between closely related organisms, variation across broader evolutionary distances suggests that only a few residues in each motif are indispensable for polymerase function. To test this, we constructed libraries of human immunodeficiency virus type-1 (HIV-1) containing random single amino acid replacements in motif B of reverse transcriptase (RT), and we used selection in culture to assess RT function. Despite the nearly absolute constancy of motif B in vivo, virus replicating in culture tolerated a range of conservative and nonconservative substitutions at 10 of the 11 amino acid positions examined. These included residues that are invariant across all retroviral subfamilies and highly conversed in diverse retroelements. Several mutants retained wild type infectivity, and serial passage experiments revealed replacements that were neutral or even beneficial to viral fitness. In addition, a number of the selected variants exhibited altered susceptibility to the nucleoside analog inhibitors AZT and 3TC. Taken together, these data indicate that HIV-1 tolerates a range of substitutions at conserved RT residues and that selection against slightly deleterious mutations (purifying selection) in vivo masks a large repertoire of viable phenotypic variants. This mutational flexibility likely contributes to HIV-1 evolution in response to changing selection pressures in infected individuals.

Amino Acid Motifs↗

PubMed2005

A semi-Markov model based on generalized Weibull distribution with an illustration for HIV disease.

Multi-state stochastic models are useful tools for studying complex dynamics such as chronic diseases. Semi-Markov models explicitly define distributions of waiting times, giving an extension of continuous time and homogeneous Markov models based implicitly on exponential distributions. This paper develops a parametric model adapted to complex medical processes. (i) We introduced a hazard function of waiting times with a U or inverse U shape. (ii) These distributions were specifically selected for each transition. (iii) The vector of covariates was also selected for each transition. We applied this method to the evolution of HIV infected patients. We used a sample of 1244 patients followed up at the hospital in Nice, France.

Adult↗

PubMed1991

[Current aspects of AIDS].

HIV epidemic is still expanding all over the world. Heterosexual transmission into the general population is of particular concern mostly in Africa and Western countries. So far, pathogenesis of the syndrome is best explained by the likely role of co-factors that interfere with the latency phase of the virus. In this setting early treatment by specific antiviral therapy such as zidovudine, will probably slow down the evolution of HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed1990

[Current aspects of AIDS].

Acquired Immunodeficiency Syndrome↗

PubMed1998

LTR and tat variability of HIV-1 isolates from patients with divergent rates of disease progression.

The genetic heterogeneity and transcription activity of the human immunodeficiency virus type 1 (HIV-1) LTR region and tat gene have been examined. Comparison involved the relevant genomic regions of viruses isolated from twenty long-term survivors and from ten typical progressors. No significant differences were observed in mutation frequencies among the two groups, although there was a significant higher proportion of synonymous substitutions in the tat gene of viruses from typical progressors. Four LTR sequences showed an insertion of 20-31 residues at the junction between the LTR Nef-coding and the LTR noncoding region. Neither these insertions nor other genetic changes found in these sequences affected the LTR transcription function, as measured in transient expression assays using transfection of both established cell lines and peripheral blood lymphocytes with plasmid DNA. The results did not allow the association of structural or functional alterations in LTR or tat with a degree of disease progression. The results reinforce the concepts of complexity of HIV-1 evolution in infected individuals, and the multifactorial nature of progression to AIDS.

Adult↗