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At least 1,171 records · Page 65Linked to original sources
PubMed2000

Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug.

Human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors (PI) is a major obstacle to the full success of combined antiretroviral therapy. High-level resistance to these compounds is the consequence of stepwise accumulation of amino acid substitutions in the HIV-1 protease (PR), following pathways that usually differ from one inhibitor to another. The selective advantage conferred by resistance mutations may depend upon several parameters: the impact of the mutation on virus infectivity in the presence or absence of drug, the nature of the drug, and its local concentration. Because drug concentrations in vivo are subject to extensive variation over time and display a markedly uneven tissue distribution, the parameters of selection for HIV-1 resistance to PI in treated patients are complex and poorly understood. In this study, we have reconstructed a large series of HIV-1 mutants that carry single or combined mutations in the PR, retracing the accumulation pathways observed in ritonavir-, indinavir-, and saquinavir-treated patients. We have then measured the phenotypic resistance and the drug-free infectivity of these mutant viruses. A deeper insight into the evolutionary value of HIV-1 PR mutants came from a novel assay system designed to measure the replicative advantage of mutant viruses as a function of drug concentration. By tracing the resultant fitness profiles, we determined the range of drug concentrations for which mutant viruses displayed a replicative advantage over the wild type and the extent of this advantage. Fitness profiles were fully consistent with the order of accumulation of resistance mutations observed in treated patients and further emphasise the key importance of local drug concentration in the patterns of selection of drug-resistant HIV-1 mutants.

Amino Acid Substitution↗
PubMedDate not supplied

[Transverse study on sex behavior associated with HIV transmission among homosexual men in Catalonia].

In 1993, a cross sectional study was carried out on the sexual behaviour of a sample of homosexual men recruited in saunas, sex shops and a gay community-beased organisation of Catalonia. A total of 551 men with an average age of 34 years and a high educational level sent in an anonymous questionnaire. In the previous 6 months the mean number of male sexual partners was 6 and for penetrative partners 3. In the previous month, 94% had had oral sex (22% with ejaculation) and 76% anal intercourse (38% without a condom and 21% with ejaculation). During sex, 51% used alcohol, 34% nitrite inhalants, 20% hashish and 10% cocaine, 61% had had the HIV test, with a self-reported HIV prevalence of 21%. 86% stated that they knew of one or more people infected by HIV or with AIDS. The high percentage of men who had unprotected anal intercourse and the high self-reported HIV prevalence highlights the need to increase efforts in AIDS prevention and research in this group. Monitoring HIV associated sexual behaviours provides valuable indicators of the evolution of the epidemic, useful for designing and evaluating preventive interventions.

Adolescent↗
PubMed1989

Sequence of a novel simian immunodeficiency virus from a wild-caught African mandrill.

Since the isolation of an HIV-2-related virus from captive macaques (SIVMAC), the origin of human immunodeficiency viruses, a much debated subject, has been attributed to monkeys. The sequence of SIVAGM, which is derived from a naturally infected African green monkey, shows equal relatedness to HIV-1 and HIV-2, suggesting that the derivation of these viruses from SIVAGM is unlikely. Recent sequence analysis of SIV from a captive sooty mangabey (SIVMAC), however, shows its close relatedness to HIV-2 and SIVMAC, indicating a possible origin of HIV-2 and SIVMAC from SIVSM (refs 4, 7, 9). We report here the sequence of a novel simian lentivirus, SIVMND, isolated from a wild-caught mandrill in Africa. It is distinct from the three other main groups, HIV-1, HIV-2/SIVMAC/SIVSM and SIVAGM, and therefore represents a fourth main group of primate lentiviruses. Phylogenetic analysis indicates that these four main virus groups might have diverged from a common ancestor at about the same time, long before the spread of AIDS in humans.

Animals↗
PubMed2005

Different epidemic potentials of the HIV-1B and C subtypes.

HIV, the cause of AIDS in humans, is characterized by great genetic heterogeneity. In particular, HIV-1 group M subtypes are responsible for most of the infections worldwide. We investigate the demographic history of HIV-1B and HIV-1C subtypes in South Africa and Brazil using both a parametric and a nonparametric approach based on coalescent theory. Our results show that although both subtypes are spreading exponentially in Brazil, the HIV-1C growth rate is about twice that of Brazilian HIV-1B or South African HIV-1C, providing evidence, for the first time, of a different epidemic potential between two HIV-1 subtypes. The present study not only may have important consequences for devising future vaccination and therapeutic strategies, but also offers additional evidence that skyline plots are indeed a simple and powerful tool for monitoring and predicting the behavior of viral epidemics.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Localized proton magnetic resonance spectroscopy of the brain in children infected with human immunodeficiency virus with and without encephalopathy.

Twenty children older than 2 y infected with human immunodeficiency virus (HIV) were examined by in vivo proton magnetic resonance spectroscopy (1H MRS) to study their cerebral metabolism and to identify metabolic profiles in relation with different stages of the disease. Patients were rated regarding their clinical and immunologic status according to the Centers for Disease Control classification and were divided into two groups: without encephalopathy (E-, n = 15) and with progressive encephalopathy (E+, n = 5). The acquisition was performed in the centrum semiovale using the short echo stimulated echo acquisition mode 20-ms sequence. The MRS profile was abnormal in all HIV-infected children compared with healthy age-matched controls (n = 7), even when magnetic resonance images were normal. A significant increase of the proportion of the lipid signals (ANOVA, p < 0.05) was found in all HIV-infected children. In addition, a significant decrease of the proportion of the N-acetylaspartate signal and a significant increase of the proportion of the myo-inositol signal (ANOVA, p < 0.05) characterized the E+ group. The principal component analysis performed on eight variables on 30 spectra confirms that the spectra of HIV-infected children differ from control spectra. The E+ group and the E- group are clearly separated on the map of subjects on the principal plane. The E- group lies in an intermediate position between the E+ group and the control group. The evolution of metabolic alterations in the brain of HIV-infected children can clearly be monitored by 1H MRS and associated with the occurrence of an encephalopathy.

AIDS Dementia Complex↗
PubMed2006

A combined empirical and mechanistic codon model.

The evolutionary selection forces acting on a protein are commonly inferred using evolutionary codon models by contrasting the rate of synonymous to nonsynonymous substitutions. Most widely used models are based on theoretical assumptions and ignore the empirical observation that distinct amino acids differ in their replacement rates. In this paper, we develop a general method that allows assimilation of empirical amino acid replacement probabilities into a codon-substitution matrix. In this way, the resulting codon model takes into account not only the transition-transversion bias and the nonsynonymous/synonymous ratio, but also the different amino acid replacement probabilities as specified in empirical amino acid matrices. Different empirical amino acid replacement matrices, such as secondary structure-specific matrices or organelle-specific matrices (e.g., mitochondria and chloroplasts), can be incorporated into the model, making it context dependent. Using a diverse set of coding DNA sequences, we show that the novel model better fits biological data as compared with either mechanistic or empirical codon models. Using the suggested model, we further analyze human immunodeficiency virus type 1 protease sequences obtained from drug-treated patients and reveal positive selection in sites that are known to confer drug resistance to the virus.

Amino Acid Substitution↗
PubMed2004

Implications of the evolution pattern of human T-cell leukemia retroviruses on their pathogenic virulence (Review).

Simian retroviruses pose a serious threat to public health, as two human pathogenic retroviruses, HIV and HTLV, have been already proved to originate from such non-human viruses. Therefore, studying their natural prevalence among wild non-human primates is important for planning strategies to prevent the emergence of additional human retroviral pathogens. This article is focused on tracing the origin and evolution of the human T-cell leukemia viruses HTLV-I and HTLV-II in comparison to that of the simian lymphotropic viruses STLV-I, STLV-II and STLV-L, which are phylo-genically classified into a common group called primate T-lymphotropic viruses (PTLV). Thus, HTLV-I and STLV-I are referred to as PTLV-I and HTLV-II and STLV-II as PTLV-II, whereas STLV-L, which is highly divergent from both HTLV types, comprises a third subgroup called PTLV-L. The phylogeny of PTLV indicates that both, HTLV-I and HTLV-II emerged from a simian origin, but their subsequent evolution continued in different patterns. HTLV-I includes 6 subtypes which evolved from STLV-I through several times of different geographic interspecies transmission between simian and human hosts. These repeated invasions to new primate species are likely to give rise to viral strains with increasing pathogenic potential. On the other hand, HTLV-II includes 4 subtypes which appear to originate from a common human ancestor virus that emerged from only one simian to human transmission, whereas the subsequent evolution of HTLV-II and STLV-II strains continued separately only within the Homo sapiens and Pan paniscus species respectively, without repeated interspecies jumps. Such evolution pattern likely involves less genetic changes and selection of viral strains with low pathogenic virulence that could co-exist with their hosts for long time. These different evolution patterns can explain the much wider implication of HTLV-I with human clinical disorders than HTLV-II. Of note, however, more recently HTLV-II started spreading much more rapidly through intravenous drug users to many geographical regions, with a 150-350 fold higher mutation rate than that of its previous strictly endemic strains. This change in the mode of the virus spread creates a serious risk for emergence of HTLV-II strains with higher virulence.

Animals↗
PubMed2006

[Pulmonary mycobacteriosis in non HIV patients, Buenos Aires City, 2003-2004].

Pulmonary disease, due to Mycobacteria other than tuberculosis, is mainly suspected in HIV + patients, or underlying other diseases. In our country, there is no updated information on the prevalence of this pulmonary disease, its treatment and evolution in immucocompetent patients. We present 10 cases of pulmonary disease due to Mycobacteria other than tuberculosis in non HIV patients: clinical-bacteriological diagnosis, treatment and evolution.

Adult↗
PubMed1999

Human Immunodeficiency Virus Reverse Transcriptase and Protease Sequence Database.

The HIV RT and Protease Sequence Database is an on-line relational database that catalogues evolutionary and drug-related human immunodeficiency virus reverse transcriptase (RT) and protease sequence variation (http://hivdb.stanford.edu). The database contains a compilation of nearly all published HIV RT and protease sequences including International Collaboration database submissions (e.g., GenBank) and sequences published in journal articles. Sequences are linked to data about the source of the sequence sample and the anti-HIV drug treatment history of the individual from whom the isolate was obtained. The database is curated and sequences are annotated with data from 180 literature references. Users can retrieve additional data and view alignments of sequences sets meeting specific criteria (e.g., treatment history, subtype, presence of a particular mutation).

Anti-HIV Agents↗
PubMed2006

Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir.

Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log(10) copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (Env) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.

Anti-HIV Agents↗
PubMed1995

[Lymphoma with skin manifestations in HIV infection: 8 cases].

INTRODUCTION: Cutaneous lymphomas occurring in HIV infection are a rare disease. Most of them are high grade lymphomas with fulminant course and poor prognosis. OBJECTIVE: Evaluate clinical and histological aspects as well as immunophenotype and evolution of these lymphomas. PATIENTS AND METHODS: Eight patients with HIV infection were studied between 1992 and 1994. The clinical and histological features were reviewed by the members of the French Study Group for Cutaneous Lymphomas. Staging procedures for lymphomas were performed in 7/8 patients. RESULTS: Seven non epidermotropic lymphomas and one mycosis fungoides were reviewed. Patients were male (6 cases) and female (2 cases); their mean age was 45 years (27-63). The mean level of CD4 T cells/mm3 was 141 (20-380). Only one patient presented with extracutaneous lesions. These lesions were similar to seronegative patients, but unusual features were observed in two cases. Histological classification showed high grade lymphomas in 6/8 cases. The immunophenotype was: T-cell lymphoma in 4 cases, B-cell lymphoma in 3 cases; it could not be determinated in one case. Six patients died. The median of survival is 8 months in this series. DISCUSSION: Our series confirms the predominance of high grade lymphomas presenting in the skin. The T-cell phenotype is more frequent. The onset of a cutaneous lymphoma has a poor prognosis in HIV infection. Most of our patients had localised disease at presentation. Therapeutic management of these lymphomas must be codified.

Adult↗
PubMed2005

HIV-1 intra-subtype superinfection rates: estimates using a structured coalescent with recombination.

Because recombination between a pair of viral genomes can occur only when both viruses are present in the same host, genealogical evidence of recombination is influenced by the rate of viral migration between infected hosts. If superinfection is rare, then recombining viral genomes will usually be more closely related to each other than to viral genomes present in other hosts and the impact of recombination on the genealogy of a sample of viruses from different hosts may be weak. We used this relationship to estimate the relative rate of intra-subtype HIV-1 superinfection in six urban populations. Comparisons of the population recombination rates estimated from the HIV-1 sequence data with population recombination rates estimated for sets of sequences simulated using a structured coalescent process suggest that intra-subtype superinfection rates in all but one of these populations may be as high as 15% of the corresponding infection rate. However, we caution that these estimates might be upwardly biased if variation in contact and mixing rates between infected hosts causes viral lineages to be concentrated in groups with higher than average superinfection rates.

Evolution, Molecular↗
PubMed2000

Analysis of the HIV-1 nef gene in five intravenous drug users with long-term nonprogressive HIV-1 infection in Italy.

Great variability in the course of human immunodeficiency virus type 1 (HIV-1) infection results from a complex interplay between host and virus factors. Some of the patients with prolonged nonprogressive infection have been reported to harbor virus variants with gross deletions in the accessory nef gene that has been implicated in in vivo pathogenicity in simian and mouse models. To investigate the role of nef-deleted HIV-1 in long-term nonprogressor (LTNP) drug addicts in Italy the nef sequence from proviral DNA was analyzed from five LTNPs and five rapid progressor controls. Only small (2-12 amino acids) in-frame deletions and insertions were detected in the N-terminal polymorphic and variable regions obtained from three LTNPs and one rapid progressor. There was no evidence of premature termination of the Nef protein and all of the identified functional motifs were well conserved in both groups. Phylogenetic analysis showed interdigitation of nef sequences obtained from LTNPs and rapid progressors. The nef sequence of one LTNP, however, diverged significantly from those of the other patients. Availability of two additional blood DNA samples obtained previously from this subject allowed to detect evolution of nef at 14-17 years of HIV-1 infection, including progressive deletions. Although alterations of nef may be relatively frequent and continue to evolve in LTNPs, this study of a small number of patients does not indicate that gross deletions or loss of functional motifs play a major role in delaying or halting disease progression in infected drug abusers in Italy.

Adolescent↗
PubMed2005

NNRTI hypersusceptibility.

Hypersusceptibility to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) is a recently described observation in which approximately 30% of HIV isolates with resistance to nucleoside reverse transcriptase inhibitors exhibit greater phenotypic susceptibility to the NNRTI class than does wild-type HIV. This increased susceptibility has been associated with better virologic outcomes in several clinical trials and observational cohorts in which NNRTI-based regimens were used. Nucleoside mutations at positions 215, 208, and 118 are associated with efavirenz hypersusceptibility, but to date, there have been no reported biochemical or structural studies on the effect of these mutations on NNRTI binding or on binding pocket conformational changes. There is currently no basis for the practical use of NNRTI hypersusceptibility to guide HIV therapeutic strategies, but it theoretically could affect the evolution of resistance in antiretroviral-naive patients who begin NNRTIs with various nucleoside backbones.

Alkynes↗
PubMed1996

Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP 266.

OBJECTIVE: To monitor the appearance of HIV-1 variants resistant to inhibition by DMP 266, a benzoxazinone non-nucleoside reverse transcriptase inhibitor using two different protocols for applying drug selective pressure in tissue culture. To compare the phenotype and genotype of viral isolates selected by each method. METHODS: MT-2 cells and fresh donor peripheral blood mononuclear cells (PBMC) were infected with HIV-1 strain RF. The MT-2 cells were infected in the presence of a 50% inhibitory concentration (IC50) of DMP 266 and the concentration was slowly increased during the selection period. The PBMC were infected for 1 week in the absence of inhibitor and then a single concentration was maintained throughout the selection period. Both cultures were passaged for approximately 4 months. Virus and cell pellets were harvested over this in vitro selection period, the RT genes amplified by polymerase chain reaction from the cell pellets, and the proviral DNAs sequenced. Isolated virus was tested for DMP 266 susceptibility in either the AIDS Clinical Trials Group/Department of Defense consensus assay or MT-2 yield reduction assay. RESULTS: Passage in MT-2 cells resulted in accumulation of three substitutions in RT (V179D, L1001, Y181C) after 24 passages associated with 1000-fold reduced susceptibility to DMP 266. In PBMC cultures treated with 0.96 microM DMP 266, virus replication was completely suppressed after 2 weeks; no regrowth occurred in the presence of compound after 10 weeks or in the absence of compound for 3 additional weeks. The 0.096 microM treated cultures had an initial 2.5-log reduction in infectious virus titre followed by rapid regrowth. Virus obtained at week 6 displayed a 28-fold reduction in susceptibility with an L1001 substitution in RT, and by week 11 displayed a 1000-fold reduction in susceptibility with an additional V1081 substitution. CONCLUSIONS: High-level resistance to DMP 266 may develop by at least two pathways and experimental conditions influence the genotype selected. The continued absence of detectable virus in the PBMC cultures grown at 0.96 microM is supportive evidence that maintaining trough plasma levels of DMP 266 which result in sustained antiviral activity in vivo may delay emergence of highly resistant viral variants. Confirmation of this hypothesis will require clinical trials.

Alkynes↗
PubMed1999

Biased nucleotide composition of the genome of HERV-K related endogenous retroviruses and its evolutionary implications.

The human genome contains a large number of sequences that belong to the HERV-K family of human endogenous retroviruses. Most of these elements are likely remnants of ancient infections by ancestral exogenous retroviruses. To obtain further insight into the evolutionary history and molecular mechanisms responsible for the diversity of the human HERV-K elements, we analyzed several aspects of their genome structure. The nucleotide composition of the HERV-K genome was found to be highly biased and asymmetric, with an abundance of the A nucleotide in the viral (+) strand. A similar trend has been reported for the genomes of several exogenous retroviruses, with different nucleotides as the preferred building block. Other genome characteristics that were reported previously for actively replicating retroviruses are also apparent for the endogenous HERV-K virus. In particular, we observed suppression of the dinucleotide CpG, which represents potential methylation sites, and a strong preference for synonymous substitutions within the open reading frame of the reverse transcriptase (RT) enzyme. Furthermore, the mutational spectrum of the HERV-K RT enzyme was evaluated by nucleotide sequence comparison of 34 available elements. Interestingly, this analysis revealed a striking similarity with the mutational pattern of the HIV-1 RT enzyme, with a preference for G-to-A and C-to-T transitions. It is proposed that the mutational bias of the HERV-K RT enzyme played a role in the shaping of this retroviral genome, which was actively replicating more than 30 million years ago. This effect can still be observed in the contemporary endogenous HERV-K elements.

Base Composition↗
PubMed2002

HIV: current opinion in escapology.

Much recent work strongly supports the hypothesis that CD8(+) T lymphocytes (CTLs) exert important immune control over HIV and so are a major selective force in its evolution. We analyse this host-pathogen interplay and focus on new data that describe the overall 'effectiveness' of CTL responses (strength, spread, specificity and 'stamina') and the mechanisms by which HIV may evade this suppressive activity. CTLs directed against HIV recognise very large numbers of distinct epitopes across the genome, are largely functional, turn over rapidly, and possess a phenotype that is distinct from CD8(+) lymphocytes specific for other viruses. Mutation of HIV epitopes that alters or abolishes CTL recognition altogether appears to be the most important immune escape mechanism, as the variation that HIV generates defies the limits of the T cell repertoire. However, this immune evasion is still only well-studied in a few patients. The rules that govern immune escape, and the ultimate limits of CTL capacity to deal with the variant epitopes that currently circulate, are not understood. This information will determine the feasibility of current vaccine approaches that, so far, make no provision for the enormous antigenic plasticity of HIV.

Adult↗