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PubMed1998

[Prevalence of human immunodeficiency virus infection in drug addicts assisted from 1991 to 1996 at a detoxification center in Castilla y Leon].

BACKGROUND: The Word Health Organization (WHO) has recommended epidemiologic surveillance of infection by the human immunodeficiency virus (HIV) in high risk populations. An important decrease has recently been observed in the prevalence of HIV infection in drug addicts in different regions in Spain with notable differences being found. The evolution of the prevalence of HIV infection in intravenous drug addicts initiating detoxication in Castilla and Leon was analyzed. METHODS: Six hundred forty-seven drug addicts (535 males and 112 females) were studied over 6 years (1991-1996) analyzing HIV seropositivity, demographic variables, drug use, age of initiation in drug consumption and route used. RESULTS: Most of the drug addicts were males (83%) with a mean age of initiation in the use of drugs of 19.6 years. Heroine was most frequently consumed in 95% of the patients. The mean length of consumption on admission was 8.6 years with no significant differences being observed in sexes. A relationship was observed between HIV infection and the lower age of initiation in drug usage with the greater the age of admission to detoxication the longer the time having consumed drugs. The prevalence of HIV infection significantly decreased in males and females from 36.8% in 1991 to 17.4% in 1996 (p < 0.0005), with this decrease being related to the change from the intravenous to the smoked route of drug intake. On multivariate analysis by logistic regression the odds ratio at one year of admission was significant (OR = 0.80), years of drug addiction (OR = 1.15), intravenous route (OR = 3.04) and female sex (OR = 2.75). CONCLUSIONS: A significant decrease has been observed in the prevalence of HIV infection in drug addicts in Castilla and León attending a therapeutic center for detoxication from 1991-1996.

Adult↗

PubMed2005

On the intra-host dynamics of HIV-1 infections.

An extension of a previously proposed theory for the pathogenesis of AIDS is presented and analyzed using a mathematical modelling approach. This theory is based on the observation that human immunodeficiency virus type 1 (HIV-1) predominantly infects and replicates in (CD4+)-T cells, and that the infection process within an infected individual is characterized by ongoing generation and selection of HIV variants with increasing reproductive capacity. This evolutionary process is considered to be the reason for the gradual loss of immunocompetence and the final destruction of the immune system observed in most patients. The extension presented here incorporates the effect of the permanently increasing susceptibility of (CD4+)-T cell clones, as a result of the evolutionary process. The presented model reproduces and possibly explains a wide variety of findings about the HIV infection process. Numerical results indicate that the effect of the initial dose is minimal, and restricted to the primary phase of infection. According to the model predictions the impact of the HIV evolutionary speed is crucial for the progression to disease. An important progression determinant is the initial infection rate, being a component of the viral reproductive capacity. An influential role in disease progression seems to be played by the initial (CD4+)-T cell count.

Algorithms↗

PubMed2000

Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E.

The human immunodeficiency virus type 1 (HIV-1) epidemic in Southeast Asia has been largely due to the emergence of clade E (HIV-1E). It has been suggested that HIV-1E is derived from a recombinant lineage of subtype A (HIV-1A) and subtype E, with multiple breakpoints along the E genome. We obtained complete genome sequences of clade E viruses from Thailand (93TH057 and 93TH065) and from the Central African Republic (90CF11697 and 90CF4071), increasing the total number of HIV-1E complete genome sequences available to seven. Phylogenetic analysis of complete genomes showed that subtypes A and E are themselves monophyletic, although together they also form a larger monophyletic group. The apparent phylogenetic incongruence at different regions of the genome that was previously taken as evidence of recombination is shown to be not statistically significant. Furthermore, simulations indicate that bootscanning and pairwise distance results, previously used as evidence for recombination, can be misleading, particularly when there are differences in substitution or evolutionary rates across the genomes of different subtypes. Taken jointly, our analyses suggest that there is inadequate support for the hypothesis that subtype E variants are derived from a recombinant lineage. In contrast, many other HIV strains claimed to have a recombinant origin, including viruses for which only a single parental strain was employed for analysis, do indeed satisfy the statistical criteria we propose. Thus, while intersubtype recombinant HIV strains are indeed circulating, the criteria for assigning a recombinant origin to viral structures should include statistical testing of alternative hypotheses to avoid inappropriate assignments that would obscure the true evolutionary properties of these viruses.

Evolution, Molecular↗

PubMed1996

Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM).

The vpr genes of human and simian immunodeficiency viruses (HIV/SIV) encode proteins which are packaged in the virus particle. HIV-1 Vpr has been shown to mediate the nuclear import of viral reverse transcription complexes in non-dividing target cells (e.g. terminally differentiated macrophages), and to alter the cell cycle and proliferation status of the infected host cell. Members of the HIV-2/SIV(SM) group encode, in addition to Vpr, a related protein called Vpx. Because these two proteins share considerable sequence similarity, it has been assumed that they also exhibit similar functions. Here, we report that the functions of Vpr and Vpx are distinct and non-redundant, although both proteins are components of the HIV-2/SIV(SM) virion and reverse transcription complex. Characterizing SIV(SM) proviruses defective in one or both genes, we found that Vpx is both necessary and sufficient for the nuclear import of the viral reverse transcription complex. In contrast, Vpr, but not Vpx, inhibited the progression of infected host cells from the G2 to the M phase of the cell cycle. Thus, two independent functions of the HIV-1 Vpr protein are encoded by separate genes in HIV-2/SIV(SM). This segregation is consistent with the conservation of these genes in HIV-2/SIV(SM) evolution, and underscores the importance of both nuclear transport and cell cycle arrest functions in primate lentivirus biology.

Animals↗

PubMed2002

Predictors of long-term increase in CD4(+) cell counts in human immunodeficiency virus-infected patients receiving a protease inhibitor-containing antiretroviral regimen.

The temporal relationships between plasma human immunodeficiency virus (HIV) RNA levels and evolution of CD4(+) cell counts was studied, using a 2-slope longitudinal mixed model, in 988 patients prospectively enrolled at the initiation of a protease inhibitor--containing regimen of antiretroviral therapy. The short-term slope (baseline through month 4) for mean change in CD4(+) cell count was +21.2 cells/mm(3)/month, and the long-term slope (month 4 through month 24) was +5.5 cells/mm(3)/month. Compared with results from patients without viral response, the long-term slope was 2.5 cells/mm(3)/month higher in patients who had plasma HIV RNA levels of <500 copies/mL at month 4 (P <.001). It was significantly lower after a rebound in plasma HIV RNA level to > or = 500 copies/mL (P <.0001), varied according to plasma HIV RNA level at the time of rebound, and was negative only when the plasma HIV RNA level at rebound was > or = 10,000 copies/mL. If CD4(+) cell counts can remain elevated despite virologic treatment failure, such a discrepant response may be transient in patients who have a high plasma HIV RNA level at the time of treatment failure.

Adult↗

PubMed2003

The evolutionary adaptation of HIV-1 to specific immunity.

Recent evidence of the evolutionary adaptation of HIV-1 to the specific immune system is reviewed. Longitudinal studies of patients show that a neutralizing antibody (NAb) response specific to autologous virus is detectable within 1-2 months of infection and that viral variants resistant to neutralization arise and spread in the viral population within the subsequent three months, and that this general pattern is repeated. There is strong evidence that amino acid replacements in gp120 glycan-binding motifs affect viral sensitivity to neutralization and are selected by NAbs. Longitudinal studies of humans have also provided good evidence of amino acid replacements in cytotoxic T lymphocyte (CTL) epitopes that allow the virus to escape detection by CTLs. But, the clearest evidence of adaptation to CTL surveillance at the molecular level comes from experiments with SIV-infected rhesus macaques. These show unequivocally that amino acid replacements in CTL epitopes are the result of positive selection and that these escape mutants have a lower class I major histocompatibility complex (MHC) binding affinity or are less likely to be recognized by CTLs than non-escape variants. To improve our ability to predict HIV's evolutionary responses to selection by the specific immune system it is suggested that future work focus on the details of the adaptive response to antibody surveillance, the temporal dynamics of specific immune responses, the relative importance of antibody and CTL selection, and the effects of superinfection, viral recombination, and viral protein functional constraints on immune escape.

Adaptation, Physiological↗

PubMed2001

Bayesian selection of continuous-time Markov chain evolutionary models.

We develop a reversible jump Markov chain Monte Carlo approach to estimating the posterior distribution of phylogenies based on aligned DNA/RNA sequences under several hierarchical evolutionary models. Using a proper, yet nontruncated and uninformative prior, we demonstrate the advantages of the Bayesian approach to hypothesis testing and estimation in phylogenetics by comparing different models for the infinitesimal rates of change among nucleotides, for the number of rate classes, and for the relationships among branch lengths. We compare the relative probabilities of these models and the appropriateness of a molecular clock using Bayes factors. Our most general model, first proposed by Tamura and Nei, parameterizes the infinitesimal change probabilities among nucleotides (A, G, C, T/U) into six parameters, consisting of three parameters for the nucleotide stationary distribution, two rate parameters for nucleotide transitions, and another parameter for nucleotide transversions. Nested models include the Hasegawa, Kishino, and Yano model with equal transition rates and the Kimura model with a uniform stationary distribution and equal transition rates. To illustrate our methods, we examine simulated data, 16S rRNA sequences from 15 contemporary eubacteria, halobacteria, eocytes, and eukaryotes, 9 primates, and the entire HIV genome of 11 isolates. We find that the Kimura model is too restrictive, that the Hasegawa, Kishino, and Yano model can be rejected for some data sets, that there is evidence for more than one rate class and a molecular clock among similar taxa, and that a molecular clock can be rejected for more distantly related taxa.

Animals↗

PubMed1999

Epidemiological considerations about retinal opportunistic infections in HIV-infected patients in France.

PURPOSE: To evaluate the evolution of the epidemiology of retinal opportunistic infections in HIV-infected patients from 1994 to 1997 and to assess the effect of HAART initiated in 1996. MATERIALS AND METHODS: Epidemiological prospective study using the data collected during ocular examinations of HIV-infected patients conducted in a single referral center specialized in HIV infection. RESULTS: From 1995 to 1997, the total number of examined HIV-infected patients and the incidence of retinitis related to CMV, VZV, tuberculosis, and toxoplasmosis decreased. The incidence of CMV retinitis, which was by far the most frequent ocular infection, fell from 6.2% to 1.2%. COMMENTS: The dramatic decrease in retinal opportunistic infections since 1996 may be related to the use of HAART. However, a close follow-up is still justified due to the increasing occurrence of resistance to protease inhibitors.

AIDS-Related Opportunistic Infections↗

PubMed2006

The essential vertebrate ABCE1 protein interacts with eukaryotic initiation factors.

The ABCE1 gene is a member of the ATP-binding cassette (ABC) multigene family and is composed of two nucleotide binding domains and an N-terminal Fe-S binding domain. The ABCE1 gene encodes a protein originally identified for its inhibition of ribonuclease L, a nuclease induced by interferon in mammalian cells. The protein is also required for the assembly of the HIV and SIV gag polypeptides. However, ABCE1 is one of the most highly conserved proteins and is found in one or two copies in all characterized eukaryotes and archaea. Yeast ABCE1/RLI1 is essential to cell division and interacts with translation initiation factors in the assembly of the pre-initiation complex. We show here that the human ABCE1 protein is essential for in vitro and in vivo translation of mRNA and that it binds to eIF2alpha and eIF5. Inhibition of the Xenopus ABCE1 arrests growth at the gastrula stage of development, consistent with a block in translation. The human ABCE1 gene contains 16 introns, and the extremely high degree of amino acid identity allows the evolution of its introns to be examined throughout eukaryotes. The demonstration that ABCE1 plays a role in vertebrate translation initiation extends the known functions of this highly conserved protein. Translation is a highly regulated process important to development and pathologies such as cancer, making ABCE1 a potential target for therapeutics. The evolutionary analysis supports a model in which an ancestral eukaryote had large number of introns and that many of these introns were lost in non-vertebrate lineages.

ATP-Binding Cassette Transporters↗

PubMed2004

Co-existence of recent and ancestral nucleotide sequences in viral quasispecies of human immunodeficiency virus type 1 patients.

In human immunodeficiency virus type 1 (HIV-1) infection, the presence of divergent nucleotide sequences within a quasispecies has been associated with double infections or samples from different times or from different tissue compartments. The authors analysed HIV-1 proviral quasispecies from PBMC of three untreated Spanish patients displaying highly divergent nucleotide sequences without evidence of double infection. The origin of these nucleotide sequences was determined by phylogenetic analysis and by dating of the different groups using a genetic divergence versus sampling year plot from a set of Spanish samples. By their short genetic distance to the node of the patient's HIV-1 phylogenetic tree and by their early date of origin, close to the seroconversion time, some groups of sequences were considered ancestral. The presence within HIV-1 quasispecies of ancestral sequences, dated up to 10 years earlier than present ones, has important consequences for in vivo viral evolution, in the pathogenesis and treatment of HIV-1 infection.

Amino Acid Sequence↗

PubMed2002

The sequential introduction of HIV-1 subtype B and CRF01AE in Singapore by sexual transmission: accelerated V3 region evolution in a subpopulation of Asian CRF01 viruses.

The rapid spread of the human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF) 01AE throughout Asia demonstrates the dynamic nature of emerging epidemics. To further characterize the dissemination of these strains regionally, we sequenced 58 strains from Singapore and found that subtype B and CRF01 were introduced separately, by homosexual and heterosexual transmission, respectively. Protein similarity scores of the Singapore CRF01, as well as all Asian strains, demonstrated a complex distribution of scores in the V3 loop--some strains had very similar V3 loop sequences, while others were highly divergent. Furthermore, we found a strong correlation between the loss of a V3 glycosylation site and the divergent strains. This suggests that loss of this glycosylation site may make the V3 loop more susceptible to immune surveillance. The identification of a rapidly evolving population of CRF01AE variants should be considered when designing new candidate vaccines and when evaluating breakthrough strains from current vaccine trials.

Acquired Immunodeficiency Syndrome↗

PubMed1999

A prospective study of the influence of HIV status on the seroreversion of serological tests for syphilis.

UNLABELLED: The evolution of serological tests for syphilis (STSs) after therapy in HIV+ patients is a major point of controversy, with possible seroreactivation and illicit seroreversion in these patients. The aim of our study was to evaluate the long-term outcome of STSs in a cohort of HIV+ male homosexuals with a history of treated syphilis as compared with HIV- controls. PATIENTS AND METHODS: Sixty-nine HIV+ male homosexuals with a documented history of treated syphilis and positive baseline treponemal tests were prospectively studied between 1986 and 1993. A medical examination, HIV staging, CD4+ cell count, VDRL, FTA-Abs tests and TPHA were performed every 6 months. Controls consisted of 49 HIV- patients with similar inclusion criteria over the same period. Comparisons between subgroups were based on chi(2) and Kruskal-Wallis tests. Analysis of negativation of the STS used the failure data methods (Kaplan-Meier, log-rank and Cox's model). RESULTS: Patients had a mean age of 38 years, a baseline CD4+ cell count of 578/mm(3), elapsed time since last syphilis of 7.5 years and a median follow-up of 4.3 years. Controls had a mean age of 42 years, elapsed time since last syphilis of 5.3 years and a median follow-up of 4.7 years. Time to seroreversion was shorter in HIV+ patients for TPHA (p = 0.009, log-rank test) and FTA-Abs test (p = 0.001, log-rank test), even after adjustment for stage of syphilis, age and time since the last episode of syphilis. The decrease in VDRL titres was not different between the 2 groups (p = 0.053, log-rank test). Seroreversion of the TPHA, FTA-Abs test and VDRL test was not significantly related to stage of syphilis, time elapsed since the last episode of syphilis, age or history of STDs in both groups. Seroreversion of the TPHA and VDRL test was not related to baseline CD4+ cell count. However, seroreversion of the FTA-Abs test was related to a low baseline CD4+ cell count (p = 0. 003). In HIV+ patients, a significant decrease in titres was noticed for TPHA, FTA-Abs test and VDRL test over time, but this time effect remained only for TPHA titres after adjustment for the CD4+ cell count. CONCLUSION: TPHA may serorevert in HIV+ patients. Thus, a non-reactive TPHA does not exclude a past syphilis infection in such patients. Evolution of the VDRL test after therapy is regular in HIV+ patients. The VDRL test remains adequate for controlling the efficacy of treatment in these patients.

Adult↗

PubMed2004

Evolutionary rate variation and RNA secondary structure prediction.

Predicting RNA secondary structure using evolutionary history can be carried out by using an alignment of related RNA sequences with conserved structure. Accurately determining evolutionary substitution rates for base pairs and single stranded nucleotides is a concern for methods based on this type of approach. Determining these rates can be hard to do reliably without a large and accurate initial alignment, which ideally also has structural annotation. Hence, one must often apply rates extracted from other RNA families with trusted alignments and structures. Here, we investigate this problem by applying rates derived from tRNA and rRNA to the prediction of the much more rapidly evolving 5'-region of HIV-1. We find that the HIV-1 prediction is in agreement with experimental data, even though the relative evolutionary rate between A and G is significantly increased, both in stem and loop regions. In addition we obtained an alignment of the 5' HIV-1 region that is more consistent with the structure than that currently in the database. We added randomized noise to the original values of the rates to investigate the stability of predictions to rate matrix deviations. We find that changes within a fairly large range still produce reliable predictions and conclude that using rates from a limited set of RNA sequences is valid over a broader range of sequences.

Algorithms↗

PubMed2003

Evolutionary characteristics of HIV type 1 variants resistant to protease inhibitors in the absence of drug-selective pressure.

To understand the evolutionary characteristics of HIV-1 variants resistant to protease inhibitors (PI), the replicating plasma virus was analyzed in three patients shifted to PI-sparing regimen after virological failure. The dynamic features of carryover mutations associated with PI resistance in the absence of selective pressure on the protease gene indicate that viral variants resistant to reverse transcriptase inhibitors and bearing mutations of the protease sequence can maintain efficient replication capacity in vivo.

Drug Resistance, Viral↗

PubMed2002

Risk to human health from a plethora of simian immunodeficiency viruses in primate bushmeat.

To assess human exposure to Simian immunodeficiency virus (SIV) in west central Africa, we looked for SIV infection in 788 monkeys that were hunted in the rainforests of Cameroon for bushmeat or kept as pets. Serologic reactivity suggesting SIV infection was found in 13 of 16 primate species, including 4 not previously known to harbor SIV. Overall, 131 sera (16.6%) reacted strongly and an additional 34 (4.3%) reacted weakly with HIV antigens. Molecular analysis identified five new phylogenetic SIV lineages. These data document for the first time that a substantial proportion of wild monkeys in Cameroon are SIV infected and that humans who hunt and handle bushmeat are exposed to a plethora of genetically highly divergent viruses.

Animals↗

PubMed2003

Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus.

Evolution and transmission of multiply drug-resistant human immunodeficiency virus type 1 (HIV-1) may limit therapeutic options as global treatment efforts expand. However, the stability of these mutants in the absence of drug selection pressure is not known. We performed a longitudinal analysis of plasma virus from a person who acquired HIV-1 that contained multiple reverse transcriptase (RT) and protease (PR) mutations. In the absence of therapy, 5 of 12 drug resistance mutations reverted in a stepwise fashion to wild type over the course of 52 weeks. Reversion of the M184V mutation alone did not change viral replicative capacity (RC), but it led to enhanced resistance to zidovudine and tenofovir. However, reversions of a second RT mutation and 3 PR mutations were associated with an increase in viral RC, and this was temporally correlated with a marked decrease in CD4 cell number. This study demonstrates the gradual stepwise back-mutation of certain drug resistance mutations in vivo in the absence of ongoing drug selection pressure. Moreover, it suggests that, despite initially impaired viral fitness, a transmitted HIV-1 isolate with multiple drug resistance mutations can evolve to develop increased RC and significant pathogenicity.

Adult↗

PubMed2005

Dynamics of enfuvirtide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy.

Enfuvirtide (ENF) is the first of a novel class of drugs that blocks HIV fusion to host cells. We analyzed the dynamics of genotypic and phenotypic resistance to ENF during and after long-term ENF therapy and its clinical implications in eight heavily treatment-experienced HIV-infected patients who underwent salvage therapy with enfuvirtide along with other antiretroviral agents. All patients showed a rapid decline in plasma HIV-RNA followed by viral rebound. Changes at codons 36, 42, 43 and/or 44 within the HR1 region of gp41 were selected in all cases, resulting in high-level phenotypic resistance to ENF, ranging from 15- to 445-fold. Both genotypic and phenotypic resistance to ENF rapidly disappeared after discontinuation of the drug, suggesting that ENF-resistant viruses may have an impaired replicative capacity.

Amino Acid Sequence↗

PubMed1999

Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease.

We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site-the properties that must be conserved in any mutant protease to retain the ability to bind and cleave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possible.

Amino Acid Sequence↗