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The clades of HIV: their origins and clinical significance.
It is over 20 years since the identification of HIV as the causative agent of AIDS. Despite the innovation and perseverance of biomedical researchers, HIV has cumulatively infected over 60 million individuals and caused the deaths of over 28 million, the majority in the developing world. There is perhaps no greater need in medical science than the development of more effective treatments for HIV and, ultimately, a protective vaccine. The spread of an extraordinary range of variants of HIV has implications for diagnosis and therapy. As the availability of antiretrovirals increases, data on the clinical response to treatment for non-B subtype infections has increasing relevance. Efficient targeting of the extreme genetic diversity of HIV-1, and an understanding of the processes underlying this, represents one of the major challenges in the control of this ongoing pandemic.
Evolution of protease and reverse transcriptase inhibitor resistance-associated mutations in HIV-1-infected protease inhibitor-treated patients with persistent low viraemia.
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Viral evolution during structured treatment interruptions in chronically human immunodeficiency virus-infected individuals.
We analyzed the evolution of the human immunodeficiency virus type 1 (HIV-1) env gene in 12 chronically infected individuals who underwent structured treatment interruptions (STIs). Analyses of length variation and of clonal sequences demonstrated highly unpredictable evolution, which may limit the strengthening of HIV-specific immune responses by STIs because of the variability in exposure to viral antigens.
Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene.
Several codon-based models for the evolution of protein-coding DNA sequences are developed that account for varying selection intensity among amino acid sites. The "neutral model" assumes two categories of sites at which amino acid replacements are either neutral or deleterious. The "positive-selection model" assumes an additional category of positively selected sites at which nonsynonymous substitutions occur at a higher rate than synonymous ones. This model is also used to identify target sites for positive selection. The models are applied to a data set of the V3 region of the HIV-1 envelope gene, sequenced at different years after the infection of one patient. The results provide strong support for variable selection intensity among amino acid sites The neutral model is rejected in favor of the positive-selection model, indicating the operation of positive selection in the region. Positively selected sites are found in both the V3 region and the flanking regions.
Correlative detection of human immunodeficiency virus (HIV) antigen p24 and Epstein-Barr virus DNA in vitro: clinical influence on HIV infection.
The existence of molecular transactivations between EBV and HIV-1, as well as reactivations of EBV latent infections in AIDS patients, have been recently documented. In order to shed more light on the putative association between EBV and HIV, and its role in the evolution to AIDS, we have determined simultaneously p24 protein and EBV DNA in culture supernatants of peripheral blood mononuclear cells from 47 individuals suspected of having HIV infection. The results of the in vitro assays were correlated with the clinical stage of the individuals and their serologic status to EBV. Statistical analysis showed a concordance between HIV infection and in vitro detection of EBV DNA (P < 0.002); particularly, a strong correlation between the presence of EBV DNA and p24 in culture was observed (P < 0.001). These results are consistent with the occurrence of viral interactions, manifested in vitro. However, in our series, the appearance of EBV DNA in culture was not concomitant with an elevation of anti-VCA IgG titers, anti-EA titers or the development of symptomatology, suggestive of a reactivation of a latent EBV infection or a progression of HIV infection. Therefore we conclude that, although interaction between both viruses may take place at the molecular level, there is no clear evidence of the repercussion that this event may have on the clinical course of HIV infection.
[The association of tuberculosis with HIV/AIDS infection in children in Romania].
The great number of AIDS cases in children in Romania, together with the high annual risk of Tb infection, created the premises for the occurrence of a relatively great number of disease cases through HIV infection/AIDS + tuberculosis, particularly in the age-group "0-5 years". Serum positive HIV children were considered as AIDS cases when tuberculosis was also associated. Twelve cases in which the infections were concomitant, transmitted through injections, constituted an exception to the point. The 12 children serum positive for HIV showed a primary musculo-cutaneous complex on their thighs, at the very place of injections. A proportion of 50% of them showed a favourable evolution under anti-Tb treatment. Most children developed primary tuberculosis aerogenically acquired, associated with AIDS. A proportion of 59.5% of them evoluted towards severe disseminated forms (milliaria, meningitis), with many deaths, and 37.8% only showed a favorable evolution under anti-tuberculosis treatment. HIV infection in children took place predominantly between 1987-1989. Tuberculosis was associated 1-2 years later, when the switching from bacillary infection into active tuberculosis was facilitated by the progressive immunodepression which is specific for AIDS. The tuberculin test with 2 IU-PPD was positive in less advanced AIDS cases but faded in children in the final stage of the syndrome or in those with severe forms of tuberculosis. Tuberculosis finding out in children with HIV infection/AIDS is however possible; therefore, skin test reaction is compulsory in all children in this category. In children with a tuberculosis cured through specific treatment in their histories, the association of HIV infection reaching AIDS stage can lead to a Tb relapse.(ABSTRACT TRUNCATED AT 250 WORDS)
Complexity and dynamics of HIV-1 quasispecies.
The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins mediate virus entry into target cells by binding receptors of the cell membrane and fusing viral and cellular structures. In particular, recent crystallographic studies have clarified the complex role of the glycoprotein gp120 in the early phase of the infection. In this context the inter- and intra-host variability of the HIV-1 gp120 poses a major problem for the development of effective methods of immunization against this virus. In the present report, the relevant aspects emerging from the study of HIV-1 variability are addressed and several methodological approaches to evaluate HIV-1 diversity discussed.
[Infection by the human immunodeficiency virus (HIV) in French Guyana. Dermato-venereologic problems].
Dermato-venereal manifestations in HIV infection and its severe evolution stage, AIDS, is of particular importance in tropical zones: We may be suspicious of the viral infection and consequently to request serologic tests to confirm it. We get an explanation of the virus transmission during heterosexual relations by the frequent occurrence and importance of the genital manifestations, leading to consider AIDS as a true sexually transmitted disease. Beside the classical opportunistic infections, the authors draw the attention to three types of manifestations: prurigo, already well known in Haïti and Africa capillary dystrophies, already reported in Haïti donovanosis that, because its epidemiological and etiopathological peculiarities, should be listed within the possible opportunistic infection if we take into consideration the regional pathological environment. In an other correction, syphilis, lepra and cutaneous leishmaniasis have to be carefully monitored, because they are capable to evaluate unexpectedly in some immunodepressive diathesis. Importance of dermato-venereal pathology in black people in tropical zone is explained by the weakness of cutaneous corneal stratum, immunologic disorders linked up to accumulated parasitic pathologies, socio-cultural life with a sexuality without complex.
Selection of human immunodeficiency virus type 1 R5 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors during severe immunodeficiency.
Early in human immunodeficiency virus 1 (HIV-1) infection CCR5-using (R5) viruses predominate. With disease progression, approximately 50% of infected individuals develop viruses able to use CXCR4. In the present work, the evolution of the biological properties of HIV-1 was studied in patients who retain viruses with an R5 phenotype despite AIDS onset. A panel of primary R5 HIV-1 isolates sequentially obtained at an asymptomatic stage and after AIDS diagnosis was examined. The viruses were selected based on our previous observation that R5 variants with reduced sensitivity to RANTES inhibition may appear during disease progression. Biological properties of the early and late R5 viruses, including infectivity, replicative capacity, impact of cationic polymer and sensitivity to inhibition by the entry inhibitors T-20 and TAK-779, were evaluated. R5 viruses isolated after AIDS onset displayed elevated replicative capacity and infectivity, and did not benefit from cationic polymer assistance during infection. Late R5 isolates also exhibited reduced sensitivity to inhibition by T-20 and TAK-779, even though the included patients were naïve to treatment with entry inhibitors and the isolates had not acquired mutations within the gp41 HR1 region. In addition, CD4+ T-cell counts at the time of R5 virus isolation correlated with infectivity, replicative capacity and sensitivity to inhibition by entry inhibitors. The results indicate that R5 HIV-1 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors may be selected for during severe immunodeficiency. At a time when the clinical use of entry inhibitors is increasing, this observation could be of importance in the optimal design of such treatments.
An African HIV-1 sequence from 1959 and implications for the origin of the epidemic.
There is considerable genetic diversity among viruses of different subtypes (designated A to J) in the major group of human immunodeficiency virus type 1 (HIV-1), the form of HIV that is dominant in the global epidemic. If available, HIV-1 sequences pre-dating the recognition of AIDS could be crucial in defining the time of origin and the subsequent evolution of these viruses in humans. The oldest known case of HIV-1 infection was reported to be that of a sailor from Manchester who died of an AIDS-like illness in 1959; however, the authenticity of this case has not been confirmed. Genetic analysis of sequences from clinical materials obtained from 1971 to 1976 from members of a Norwegian family infected earlier than 1971 showed that they carried viruses of the HIV-1 outlier group, a variant form that is mainly restricted to West Africa. Here we report the amplification and characterization of viral sequences from a 1959 African plasma sample that was previously found to be HIV-1 seropositive. Multiple phylogenetic analyses not only authenticate this case as the oldest known HIV-1 infection, but also place its viral sequence near the ancestral node of subtypes B and D in the major group, indicating that these HIV-1 subtypes, and perhaps all major-group viruses, may have evolved from a single introduction into the African population not long before 1959.
Hierarchical phylogenetic models for analyzing multipartite sequence data.
Debate exists over how to incorporate information from multipartite sequence data in phylogenetic analyses. Strict combined-data approaches argue for concatenation of all partitions and estimation of one evolutionary history, maximizing the explanatory power of the data. Consensus/independence approaches endorse a two-step procedure where partitions are analyzed independently and then a consensus is determined from the multiple results. Mixtures across the model space of a strict combined-data approach and a priori independent parameters are popular methods to integrate these methods. We propose an alternative middle ground by constructing a Bayesian hierarchical phylogenetic model. Our hierarchical framework enables researchers to pool information across data partitions to improve estimate precision in individual partitions while permitting estimation and testing of tendencies in across-partition quantities. Such across-partition quantities include the distribution from which individual topologies relating the sequences within a partition are drawn. We propose standard hierarchical priors on continuous evolutionary parameters across partitions, while the structure on topologies varies depending on the research problem. We illustrate our model with three examples. We first explore the evolutionary history of the guinea pig (Cavia porcellus) using alignments of 13 mitochondrial genes. The hierarchical model returns substantially more precise continuous parameter estimates than an independent parameter approach without losing the salient features of the data. Second, we analyze the frequency of horizontal gene transfer using 50 prokaryotic genes. We assume an unknown species-level topology and allow individual gene topologies to differ from this with a small estimable probability. Simultaneously inferring the species and individual gene topologies returns a transfer frequency of 17%. We also examine HIV sequences longitudinally sampled from HIV+ patients. We ask whether posttreatment development of CCR5 coreceptor virus represents concerted evolution from middisease CXCR4 virus or reemergence of initial infecting CCR5 virus. The hierarchical model pools partitions from multiple unrelated patients by assuming that the topology for each patient is drawn from a multinomial distribution with unknown probabilities. Preliminary results suggest evolution and not reemergence.
[Virological diagnosis and follow-up of HIV infection. State of the art and situation in Tunisia].
Human immunodeficiency virus (HIV) is a retrovirus infecting approximatively 40 million people worldwide. HIV is characterized by a great variability with epidemiological, diagnostic and therapeutic implications. The course of infection goes through three stages (acute infection, clinical latency and AIDS) with the evolution of virological markers (anti-HIV antibodies, p24 antigenemia, plasma RNA and proviral DNA). Direct virological diagnosis is mainly based on molecular tools allowing viral genome detection and amplification with specific primers and nucleic probes besides p24 antigenemia detection, and more rarely viral culture. Antigenic properties of viral proteins elicit in infected patients antibody synthesis, which is detected using serology (ELISA and Western blot tests). The follow-up of infected patients is carried out with plasma HIV-1 RNA quantitation and phenotypic or genotypic characterization of variant isolates. Virological tests are prescribed according to clinical presentation (screening, acute infection, newborn from HIV-infected mother). Most of these virological tools are available in Tunisia, allowing both diagnosis of HIV infection and monitoring of infected individuals. Regarding diagnostic tests indication and interpretation, multidisciplinary concertation is hopeful in order to optimize patient management.
Five-year immunological outcome of highly active antiretroviral treatment in a clinical setting: results from a single HIV treatment centre.
Our objective was to study the evolution of CD4 cell count five years after starting highly active antiretroviral treatment (HAART) in a clinical setting. The study was performed at the HIV outpatient clinic, Institute of Tropical Medicine, Antwerp. All patients (n = 225) who started HAART in 1997, who had a CD4 cell count within six months prior to starting HAART and who were subsequently followed for at least two years were included. Change in CD4 cell count after start of HAART and the influence of patient and clinical factors were investigated using graphical exploration, endpoint analysis and mixed-effects linear regression. The mean CD4 cell count at start of HAART was 280 cells/mm(3). At the five-year endpoint of the study the mean increase in CD4 cell count was 333 cells/mm(3), while 79% of the patients had a viral load less than 400 copies/mL. There was a significant negative correlation between increase in CD4 cell count at five years and time since first positive HIV test at start of HAART (P = 0.021). Patients who ever had a HAART interruption of more than seven days had a significantly lower increase in CD4 cell count than those who did not (225 cells/mm(3) compared with 438 cells/mm(3); P < 0.001). A mixed-effects linear regression model additionally suggested a significant impact of exposure to antiretrovirals prior to HAART (P = 0.03). Overall, the recovery of CD4 cell count after five years of HAART is good, although therapy interruptions have an important negative impact.
Virological and immunological characteristics of HIV treatment failure.
BACKGROUND: Resistance to antiretroviral treatment is prevalent. There is limited knowledge of the determinants of disease evolution in subjects infected with multidrug-resistant HIV (MDR-HIV). METHODS: Infectivity, replication, chemokine receptor usage, and env, gag, protease and reverse transcriptase sequence analysis was performed for MDR-HIV isolates from 14 HIV-infected individuals and compared to wild-type HIV isolates from individuals naive to antiretroviral treatment. Expression of CD45RO/RA, Ki67 and interferon-gamma and CD4 proliferative response to various antigens was determined for individuals infected with MDR-HIV and compared to that in individuals with optimal suppression of viral replication. RESULTS: Infectivity and replication are diminished for various MDR-HIV isolates, usually in the context of an increase in CD4 and CD4+CD45RA+ T-cell counts. However, a number of MDR-HIV isolates are associated with high in vivo viraemia and pronounced immunosuppression, and display in vitro levels of infectivity and replication comparable to those of wild-type strains. No specific genetic sequence or chemokine receptor usage predicted the fitness of an MDR isolate. CONCLUSIONS: Despite the biological diversity of resistant viruses and the range of host responses observed, our descriptive analysis indicates that viral factors play a role in determining the degree of immune damage observed in the context of MDR-HIV infection.
Viruses in the pathogenesis of Kaposi's sarcoma--a review.
Kaposi's sarcoma (KS) is the most frequent malignancy in AIDS patients. Epidemiological studies indicate that a sexually transmitted infections agent other than HIV is involved in the evolution of KS. This "KS agent" may induce a cascade of cytokines which promote the development of the tumor in an autocrine and paracrine mechanism. In this review article several viruses, especially the recently discovered Kaposi's sarcoma herpesvirus (KSHV or HHV-8), are discussed as possible KS agents, and different scenarios of the viral contribution to the pathogenesis of AIDS-associated KS are presented.
Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS.
There are significant associations between possession of certain HLA class I alleles and rate of progression to AIDS. Immunological data provide an explanatory mechanism for this relationship. Patients with HLA types associated with rapid disease progression recognize a significantly smaller fraction of their known repertoire of viral epitopes than do patients with HLA types associated with slow progression. Population frequency of HLA types (or supertypes) and their capacity to elicit cytotoxic T lymphocyte responses are also negatively correlated. These data provide an immunological mechanism to explain HLA-related risk of progression to AIDS and emphasize the central role of viral evolution in the pathogenesis of HIV.
Antibody vs. HIV in a clash of evolutionary titans.
HIV has evolved many strategies to avoid neutralizing antibody responses, particularly to conserved regions on the external glycoprotein spikes of the virus. Nevertheless, a small number of antibodies have been evolved by the human immune system to recognize conserved parts of the glycoproteins, and therefore, have broadly neutralizing cross-strain activities. These antibodies constitute important tools in the quest to design immunogens that can elicit broadly neutralizing antibodies in humans and hence contribute to an effective HIV vaccine. Crystallographic analyses of the antibodies, in many cases in an antigen-complexed form, have revealed novel and, in some instances, remarkable structural adaptations to attain virus recognition. Antibodies, like HIV, can evolve relatively rapidly through mutation and selection. It seems that the structures of these broadly neutralizing antibodies bear witness to a heroic struggle between two titans of rapid evolution.