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PubMed2005

Evolution of relative synonymous codon usage in Human Immunodeficiency Virus type-1.

Mutation in Human Immunodeficiency Virus type-1 (HIV-1) is extremely rapid, a consequence of a low-fidelity viral reverse transcription process. The envelope gene has been shown to accumulate substitutions at a rate of approximately 1% per year and can frequently spend a long time in the host (approximately 10 years). The relative synonymous codon usage (RSCU) in HIV-1 is known to be different from that of the human host. However, by reengineering the protein coding sequences of HIV-1 to reflect the RSCU patterns observed in humans, a large increase in protein expression is observed. It is reasonable to suggest that within a host there may be a selective drive for change in the RSCU of HIV-1 towards human RSCU. To test this hypothesis we analyzed HIV-1 partial envelope sequences from eight patients sampled serially in time. For each sequence, an RSCU table was constructed. Sequences were labelled as "early" or "late" depending on whether they were sampled before or after the mid-point of the study. Using the RSCU values as descriptor variables, a Principal Components Analysis (PCA) was performed. The first three components clearly discriminated between early and late sequences. We also constructed pooled groupwise RSCU tables for early and late sequences. The viral RSCU values of each of the groups were correlated with human RSCU. If there is selection for host-adaptation in RSCU, we expect that "late" viral RSCUs would tend to be more highly correlated with human RSCU than "early" viral RSCUs. In fact, tests of significance suggest that this is the case. However, closer examination of the data revealed that the apparent trend towards human RSCU can be attributed to the homogenization of the codon usage by mutation pressure rather than host adaptation.

Algorithms↗

PubMed1991

[Mortality and HIV infection in a group of intravenous heroin addicts from 1985 to 1989].

One hundred and eighty-seven heroin addicts resident in Valle Seriana Superiore were monitored from July 1985 to July 1989. This sample was representative of a total population of drug addicts estimated at some 350 subjects, 90 of whom (48.1%) were HIV-positive in Elisa assays and Western blot control tests. Six patients (3.2%) died; 3 of whom (3%) were HIV-positive and 3 (3.3%) were HIVab-negative. The most frequent cause of death (59%) was heroin overdose, which occurred in both HIV-positive and negative subjects, showing that the fear of contracting the disease or its possible evolution is not a deterrent in modifying risk behaviour. During the four years of the study, 5 (5.5%) of the HIV-positive patients developed confirmed AIDS. Only one patient died from AIDS, thus confirming the current risk of death as being 1.1% in seropositive patients. An increase in mortality due to AIDS is expected in the future, in line with the current prevalent mortality rate due to heroin overdose.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Adaptation to different human populations by HIV-1 revealed by codon-based analyses.

Several codon-based methods are available for detecting adaptive evolution in protein-coding sequences, but to date none specifically identify sites that are selected differentially in two populations, although such comparisons between populations have been historically useful in identifying the action of natural selection. We have developed two fixed effects maximum likelihood methods: one for identifying codon positions showing selection patterns that persist in a population and another for detecting whether selection is operating differentially on individual codons of a gene sampled from two different populations. Applying these methods to two HIV populations infecting genetically distinct human hosts, we have found that few of the positively selected amino acid sites persist in the population; the other changes are detected only at the tips of the phylogenetic tree and appear deleterious in the long term. Additionally, we have identified seven amino acid sites in protease and reverse transcriptase that are selected differentially in the two samples, demonstrating specific population-level adaptation of HIV to human populations.

Adaptation, Physiological↗

PubMed2002

Mutational analysis of HIV-1 long terminal repeats to explore the relative contribution of reverse transcriptase and RNA polymerase II to viral mutagenesis.

HIV-1 evolves rapidly, which is thought to result from one or more error-prone steps in the virus life cycle. Because HIV-1 reverse transcriptase (RT) does not possess 3'- to 5'-exonucleolytic proofreading activity and because RT has been shown to be error-prone in cell free systems, it should be an important contributor to the high rate of HIV-1 mutation. However, because RNA polymerase II (pol II) synthesizes viral RNA, it might also contribute significantly to HIV-1 mutagenesis. To assess the relative contributions of RT and RNA pol II to HIV-1 mutagenesis, a system was established to study the rate and nature of mutations in HIV-1 long terminal repeats (LTRs). Owing to the unique nature of replication at the ends of the viral genome, mutational analysis of retroviral LTRs provides an opportunity to evaluate the relative contribution of HIV-1 RT and RNA pol II to viral mutagenesis. Mutational analysis was performed on both LTRs of 215 proviruses, restricted to a single cycle of replication, employing single-stranded conformational polymorphism and DNA sequencing allowing direct identification of mutations in the absence of selection and within autologous viral sequences. A total of 21 independent mutations was identified. Ten mutations were observed in both LTRs, which could have been introduced by either RT or RNA pol II, whereas the other eleven mutations were only present in a single LTR and could only have been introduced by RT. This provides the first direct evidence that HIV-1 RT contributes significantly to HIV-1 mutagenesis and is likely to be the primary engine for HIV-1 mutagenesis. Moreover, mutations were observed at the U3-R border, but the nature of the mutations and their frequency differed from experiments performed using cell-free systems suggesting that other viral and/or cellular factors contribute to fidelity at the ends of the viral genome.

Base Sequence↗

PubMed2006

Saquinavir/Ritonavir: its evolution and current treatment role.

As formulations and combinations of drugs to treat HIV infection improve, physicians are better able to offer therapies that reduce pill burden while maintaining safety and effective viral control. Saquinavir mesylate, the first protease inhibitor (PI) approved by the FDA, was recently reformulated to reduce pill burden and is meant to be used in regimens boosted with low-dose ritonavir. This article reviews ritonavir-enhanced or "boosted" saquinavir regimens and the clinical trials using this PI combination and discusses potential advantages of and opportunities with the current use of these regimens.

Biological Availability↗

PubMed2006

Antiviral efficacy and genotypic resistance patterns of combination therapy with stavudine/tenofovir in highly active antiretroviral therapy experienced patients.

OBJECTIVES: To evaluate antiviral efficacy of stavudine/tenofovir (d4T/TDF) backbone combination in late-line antiretroviral therapy, and to assess clinical and virological determinants of treatment success. DESIGN: Multicentric retrospective analysis on patients starting d4T/TDF after highly active antiretroviral therapy (HAART) failure. METHODS: The primary endpoint was the change in plasma HIV-1 RNA from the baseline (time of d4T/TDF initiation) to 6 months of therapy; secondary endpoint was the risk of virological failure. RESULTS: Among 172 patients included, a mean change in HIV-1 RNA of -1.69 (+1.23) and -1.53 (+1.43) log10 cp/ml was observed respectively at weeks 24 and 48 after starting d4T/TDF combination. Any single type-1 thymidine analogue mutation (TAM; M41L, L210W, T215Y) had a negative effort on the change in HIV RNA at 6 months, whereas among type-2 TAMs (D67N, K70R, K219Q), only D67N showed a trend for a negative effect. Presence of M184V mutation was related with a greater reduction in HIV RNA during d4T/TDF exposure. The risk of virological failure at 6 months after d4T/TDF starting was 22%. Type-1 TAMs were associated with a greater risk of failure (adjusted hazard ratio [HR]=1.65; 95% confidence interval [CI] 1.19-2.29). Conversely, M184V showed a protective effect. In 17 genotypic tests available at failure, no K65R mutation was detected, whereas a trend for an increasing prevalence of d4T-associated mutations was found. CONCLUSIONS: Combining TDF with a thymidine analogue as d4T may be effective as component of antiretroviral rescue regimens in HIV-infected patients with previous exposure to nucleoside analogue reverse transcriptase inhibitor. Previous selection of type-1 TAMs induces a detrimental effect over virological response.

Adenine↗

PubMed1997

[Longitudinal echocardiographic study of HIV positive patients].

BACKGROUND: From May 1992 to June 1996 the authors have studied a group of 39 subjects with positive anti-HIV, with echo 2D color Doppler examination, to evaluate with semi-annual controls, the wide variety of cardiac complications in the various phases of clinical evolution of the illness. METHODS: At the moment of recruiting, all the subjects with HIV infection were asymptomatic A1 (HIV + As). The patients whose average age was 29 +/- 5, were composed of 60% drug addicts, 17% homosexuals, 8% haemophiliacs and for the 15% heterosexual. RESULTS: The most frequent cardiac complications are represented by hypokinesia of the left ventricle (h-aLV) and by pericardial effusion (PE); more rarely of endocardial vegetations (EV), dilatation of the left ventricle (dLV) and tricuspid insufficiency (TI). The entity of damage and the number of cases observed, are correlated with the grade of clinical severity of the illness. CONCLUSIONS: In accordance with the literature data, cardiac pathologies, particularly in the first phases of the illness, are asymptomatic or paucisymptomatic, making the clinical-instrumental observation of the patient useful also in cardiology.

AIDS-Related Opportunistic Infections↗

PubMed1999

Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes.

The human AIDS viruses human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) represent cross-species (zoonotic) infections. Although the primate reservoir of HIV-2 has been clearly identified as the sooty mangabey (Cercocebus atys), the origin of HIV-1 remains uncertain. Viruses related to HIV-1 have been isolated from the common chimpanzee (Pan troglodytes), but only three such SIVcpz infections have been documented, one of which involved a virus so divergent that it might represent a different primate lentiviral lineage. In a search for the HIV-1 reservoir, we have now sequenced the genome of a new SIVcpzstrain (SIVcpzUS) and have determined, by mitochondrial DNA analysis, the subspecies identity of all known SIVcpz-infected chimpanzees. We find that two chimpanzee subspecies in Africa, the central P. t. troglodytes and the eastern P. t. schweinfurthii, harbour SIVcpz and that their respective viruses form two highly divergent (but subspecies-specific) phylogenetic lineages. All HIV-1 strains known to infect man, including HIV-1 groups M, N and O, are closely related to just one of these SIVcpz lineages, that found in P. t. troglodytes. Moreover, we find that HIV-1 group N is a mosaic of SIVcpzUS- and HIV-1-related sequences, indicating an ancestral recombination event in a chimpanzee host. These results, together with the observation that the natural range of P. t. troglodytes coincides uniquely with areas of HIV-1 group M, N and O endemicity, indicate that P. t. troglodytes is the primary reservoir for HIV-1 and has been the source of at least three independent introductions of SIVcpz into the human population.

Acquired Immunodeficiency Syndrome↗

PubMed2004

The molecular population genetics of HIV-1 group O.

HIV-1 group O originated through cross-species transmission of SIV from chimpanzees to humans and has established a relatively low prevalence in Central Africa. Here, we infer the population genetics and epidemic history of HIV-1 group O from viral gene sequence data and evaluate the effect of variable evolutionary rates and recombination on our estimates. First, model selection tools were used to specify suitable evolutionary and coalescent models for HIV group O. Second, divergence times and population genetic parameters were estimated in a Bayesian framework using Markov chain Monte Carlo sampling, under both strict and relaxed molecular clock methods. Our results date the origin of the group O radiation to around 1920 (1890-1940), a time frame similar to that estimated for HIV-1 group M. However, group O infections, which remain almost wholly restricted to Cameroon, show a slower rate of exponential growth during the twentieth century, explaining their lower current prevalence. To explore the effect of recombination, the Bayesian framework is extended to incorporate multiple unlinked loci. Although recombination can bias estimates of the time to the most recent common ancestor, this effect does not appear to be important for HIV-1 group O. In addition, we show that evolutionary rate estimates for different HIV genes accurately reflect differential selective constraints along the HIV genome.

Bayes Theorem↗

PubMedDate not supplied

[Therapeutic potential of Ro 5-3335. New active benzodiazepine in vitro against HIV-1 viruses resistant or non-resistant to AZT].

Ro 5-3335 is a new benzodiazepine highly active in vitro (IC50 = 0.1-1.0 microM [corrected]) against HIV-1 viruses of AIDS resistant or non-resistant to zidovudine (AZT). It is also active against HIV-2. Ro 5-3335 is original by its mechanism of action, acting on the trans-activation factor of transcription (TAT) and non on the reverse transcriptase. Such as, it could prevent proviral DNA to express in both evolutive and silent AIDS resistant or non-resistant to AZT or to other anti-reverse transcriptase series. In addition, in antagonizing extracellular TAT's actions, Ro 5-3335 could alleviate the syndrome commonly associated with AIDS as Kaposi's syndrome. In rodent test, Ro 5-3335 has no diazepam-like central effects and presents in comparison to AZT a more favorable therapeutic index. In dog, the elimination half-life, peak concentration and availability are 2 h, 0.8 microM and 85% respectively, after a 1 mg.kg-1 oral dose of Ro 5-3335. Theoretically, Ro 5-3335 and now its analogue Ro 24-7429 seem to possess all virtues to antagonize evolutive and latent AIDS. Its arrival is timely to cope with the ever increasing resistance phenomena, lengthy development of AIDS vaccines, exponential contamination of populations worldwide and last but not least possibly to impede evolutions of the disease. Ability to manipulate TAT-mediated activation of HIV-1 genes paves the ways to study conceivable corrections of abnormal gene expressions of neurotransmitters, hormones, oncogenes and key enzymes.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Activities and substrate specificity of the evolutionarily conserved central domain of retroviral integrase.

The retroviral integrase (IN) is a virus-encoded enzyme that is essential for insertion of viral DNA into the host chromosome. In order to map and define the properties of a minimal functional domain for this unique viral enzyme, a series of N- and C-terminal deletions of both Rous sarcoma virus (RSV) and human immunodeficiency virus (HIV) INs were constructed. The RSV IN deletion mutants were first tested for their ability to remove two nucleotides from the end of a substrate representing the terminus of viral DNA in order to assess the contribution of N and C regions towards this reaction, referred to as processing. The results suggest that C-terminal amino acids of the intact RSV protein are required to maintain specificity of the processing reaction. Though deficient for processing, the RSV deletion mutants exhibited a secondary endonucleolytic activity that was indistinguishable from that of wild-type IN, demonstrating that all retained some enzymatic activity. RSV, and a larger set of HIV-1, IN deletion mutants were then tested for their ability to perform an intramolecular, concerted cleavage-ligation reaction using an oligodeoxynucleotide substrate that mimics the intermediate viral-host DNA junction found prior to the final step of covalent closure. The composite results from such analyses define a minimal functional central region of approximately 140 amino acids for each enzyme that includes the highly conserved D,D(35)E domain. Results with HIV-1 and HIV-2 IN also indicate that the efficiency of concerted cleavage-ligation depends upon the presence of CA/GT base pairs within the viral component of the DNA substrate at the reaction site. Even the isolated central region of HIV-1 IN exhibited this sequence requirement for optimal activity. We conclude that this evolutionarily conserved central region of IN not only encodes residues that are required for the catalytic activity of the enzyme but also harbors some or all of the determinants responsible for recognition of the CA/GT dinucleotides that are present at the ends of all retroviral DNAs.

Avian Sarcoma Viruses↗

PubMed2004

Effect of polymorphisms on the replicative capacity of protease inhibitor-resistant HIV-1 variants under drug pressure.

The role of drug pressure on the replicative capacity of protease inhibitor-resistant HIV-1 variants and the contribution of a common amino-acid polymorphism in the protease gene (L63P) to this process were investigated. Using HIV-1 variants resistant to the protease inhibitors saquinavir (G48V/L90M) or indinavir (A71V/V82T/I84V), viral replication was studied in the presence or absence of inhibitor and a mutation at position 63. The initial changes diminished enzyme function of the protease and reduced replicative capacity for both virus mutants. Addition of the respective inhibitor blocked the wild-type, but was also able to delay the replication kinetics of either mutant, revealing the limits of resistance. Importantly, the polymorphic change L63P, although not conferring inhibitor resistance by itself, provided a significant replication benefit to both mutant viruses, particularly under drug pressure, and may reveal a far-reaching compensating power of polymorphic changes. This may drive evolution and the directed selection of protease inhibitor-resistant HIV-1 variants, a finding with significant clinical and diagnostic implications.

Amino Acid Sequence↗

PubMed1996

[Polyneuropathies of pregnancy. Clinical neurophysiological, and anatomo-pathological study apropos of 38 cases collected at the Neurology Clinic of the the Fann University Hospital Center].

Authors are studying the clinical, electrophysiological, and anatomical aspects of polyneuropathies of 28 observations in Clinic Neurologic of Fann, the onset occurred in pregnancy. Relations with Tropical Neuro-myelopathies (TNM) are emphasized. 28 observations concerning young women between 17 and 35 years old, the onset of neuropathy occurred in pregnancy or immediate post-partum period or miscarriage. Electrophysiological examination and neuromuscular biopsy are performed. Current neuropathological technics were done with the biopsy material including teased fiber and electron microscope examination. Three clinical forms were individualized: polyneuritis form; polyradiculoneuritis form, and the combined sclerosis of the spinal cord. Aetiological conditions were discussed for each clinical form with their evolution course. None of these patients had positive retroviral serology (HIV or HTLV-I). No clinical particularity was found with polyneuritis form; polyradiculoneuritis form was of axonal type; combined sclerosis of the spinal cord showed demyelinating neuropathy. A good electrical and clinico-anatomical correlation was found in each clinical form. Clinical, biological, electrophysiological and anatomical aspects are discussed. Pregnant polyneuropathies are bad known clinical entity, but are frequent in women of childbearing age (21% of PN and 38.7% of TNM) in young women. 50% are from 28 to 36 years old multiparous. Three clinical forms have identical features with TNM with a poor economic and nutritional condition but no relation with HTLV-I. Clinical, electrophysiological and histological finding are correlated with evolution and prognosis.

Adolescent↗

PubMedDate not supplied

Mucosal immune response to Human Papilloma Virus (HPV) infection in HIV positive women.

Mucosal immunity plays a central role in the control of genital human papilloma virus (HPV) infection. HIV infection is associated with higher risks of HPV-induced neoplasias. Prevalence, incidence and evolution of genital HPV lesions are correlated with the level of immunodepression. Several changes of the local immune response in the genital tract of HIV infected women have been demonstrated. The influence of HIV on the production of some immunoregulatory cytokines appears of particular interest. The shift from the helper T cells type 1 (Th1) to the helper T cells type 2 (Th2) immune response, which determines the downregulation of the cell-mediated immunity, may explain the frequent loss of immunologic control of HPV and its oncological complications

Down-Regulation↗

PubMed2000

Timing the ancestor of the HIV-1 pandemic strains.

HIV-1 sequences were analyzed to estimate the timing of the ancestral sequence of the main group of HIV-1, the strains responsible for the AIDS pandemic. Using parallel supercomputers and assuming a constant rate of evolution, we applied maximum-likelihood phylogenetic methods to unprecedented amounts of data for this calculation. We validated our approach by correctly estimating the timing of two historically documented points. Using a comprehensive full-length envelope sequence alignment, we estimated the date of the last common ancestor of the main group of HIV-1 to be 1931 (1915-41). Analysis of a gag gene alignment, subregions of envelope including additional sequences, and a method that relaxed the assumption of a strict molecular clock also supported these results.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Recombination: Multiply infected spleen cells in HIV patients.

The genome of the human immunodeficiency virus is highly prone to recombination, although it is not obvious whether recombinants arise infrequently or whether they are constantly being spawned but escape identification because of the massive and rapid turnover of virus particles. Here we use fluorescence in situ hybridization to estimate the number of proviruses harboured by individual splenocytes from two HIV patients, and determine the extent of recombination by sequencing amplified DNA from these cells. We find an average of three or four proviruses per cell and evidence for huge numbers of recombinants and extensive genetic variation. Although this creates problems for phylogenetic analyses, which ignore recombination effects, the intracellular variation may help to broaden immune recognition.

Amino Acid Sequence↗

PubMed1995

Viral resistance and the selection of antiretroviral combinations.

Mounting scientific evidence suggests that viral replication and evolution of diversification, with the resulting emergence of variants including drug-resistant strains, is responsible for the gradual destruction of the immune system and is the mechanism of disease progression in HIV-infected patients. Monotherapy does not give long-term suppression of viral replication and evolution, and combination therapy is viewed as a potentially more effective long-term approach based on increased and more durable suppression of HIV replication. Because of the large number of drugs that could be used in combination therapy regimens, it is important to investigate, in clinical studies, only those combinations likely to be most effective. In vitro studies are therefore critical in the selection of such combinations. Resistance mutations to many antiretroviral agents have been documented and their patterns of emergence elucidated. A number of studies have since demonstrated the phenomenon of cross-resistance, in which resistant virus emerging under the selective pressure of one therapy is also cross-resistant to a second antiviral agent. This information can be used to avoid combining agents to which cross-resistance can occur. Suppression or "phenotypic reversal" of zidovudine resistance by the lamivudine-resistance mutation at codon 184 has been demonstrated in in vitro studies. It is encouraging that this finding has led to the clinical evaluation of these two agents with promising results. Moreover, in vitro scientific data are critical in facilitating the identification of potentially effective combination therapies.

Antiviral Agents↗

PubMed2001

Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies.

When chronic hepatitis C virus (HCV) infections are complicated by acquisition of human immunodeficiency virus (HIV), liver disease appears to accelerate and serum levels of HCV RNA may rise. We hypothesized that HIV might affect the HCV quasispecies by decreasing both complexity (if HIV-induced immunosuppression lessens pressure for selecting HCV substitutions) and the ratio of nonsynonymous (d(N)) to synonymous (d(S)) substitutions, because d(N) may be lower (if there is less selective pressure). To test this hypothesis, we studied the evolution of HCV sequences in 10 persons with chronic HCV infection who seroconverted to HIV and, over the next 3 years, had slow or rapid progression of HIV-associated disease. From each subject, four serum specimens were selected with reference to HIV seroconversion: (i) more than 2 years prior, (ii) less than 2 years prior, (iii) less than 2 years after, and (iv) more than 2 years after. The HCV quasispecies in these specimens was characterized by generating clones containing 1 kb of cDNA that spanned the E1 gene and the E2 hypervariable region 1 (HVR1), followed by analysis of clonal frequencies (via electrophoretic migration) and nucleotide sequences. We examined 1,320 cDNA clones (33 per time point) and 287 sequences (median of 7 per time point). We observed a trend toward lower d(N)/d(S) after HIV seroconversion in 7 of 10 subjects and lower d(N)/d(S) in those with rapid HIV disease progression. However, the magnitude of these differences was small. These results are consistent with the hypothesis that HIV infection alters the HCV quasispecies, but the number of subjects and observation time may be too low to characterize the full effect.

Adult↗