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PubMed2001

Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir.

Variable drug penetration of antiretroviral drugs into the genital tract may contribute to the differential evolution of HIV and the emergence of drug resistance. This, in turn, may have an impact on the sexual transmission of resistant HIV in patients treated with antiretroviral drugs. We have measured concentrations of the HIV-1 protease inhibitors indinavir, ritonavir and saquinavir in the blood plasma (BP) and seminal plasma (SP) of 23 HIV-1-positive men. Forty-five time-matched blood and semen samples were obtained. SP concentrations of indinavir exceeded the EC95 of indinavir, corrected for protein binding, of 42 ng/mL at all time intervals. In contrast, the median ritonavir and saquinavir SP concentrations were below the relevant EC95 at all times post drug ingestion. The median SP:BP concentration ratios for indinavir were 0.6, 0.8 and 1.4, respectively, at 0-2, 2-6 and 6-8 h post-drug ingestion. In contrast, the median SP:BP concentration ratios at 0-3, 3-9 and 9-12 h post-drug ingestion were <0.02, <0.04 and <0.04, respectively, for both ritonavir and saquinavir. These differences justify further study of HIV-1 evolution and development of resistance in the genital tract of men taking these anti-HIV drugs.

Adult↗
PubMed2000

Early changes in quasispecies repertoire in HIV-infected infants: correlation with disease progression.

The evolution of HIV-1 quasispecies in patients during the first year of life was investigated in 10 vertically infected infants, using heteroduplex analysis of the V3-V5 region of env. Four subjects, who showed little viral evolution during the period of the study, had rapid progression of disease and early loss of CD4(+) cells. The remaining six subjects, who were slow progressors, evolved new viral variants within 6 months, and in one case by 1 month of age. Of the four patients who were PCR positive at birth, one was infected with multiple HIV-1 variants. These results show that in HIV-infected children, multiple variants may initiate infection and early quasispecies diversification is associated with a favorable clinical outcome.

Disease Progression↗
PubMed1994

Identification of three feline immunodeficiency virus (FIV) env gene subtypes and comparison of the FIV and human immunodeficiency virus type 1 evolutionary patterns.

Feline immunodeficiency virus (FIV) is a lentivirus associated with AIDS-like illnesses in cats. As such, FIV appears to be a feline analog of human immunodeficiency virus (HIV). A hallmark of HIV infection is the large degree of viral genetic diversity that can develop within an infected individual and the even greater and continually increasing level of diversity among virus isolates from different individuals. Our goal in this study was to determine patterns of FIV genetic diversity by focusing on a 684-nucleotide region encompassing variable regions V3, V4, and V5 of the FIV env gene in order to establish parallels and distinctions between FIV and HIV type 1 (HIV-1). Our data demonstrate that, like HIV-1, FIV can be separated into distinct envelope sequence subtypes (three are described here). Similar to that found for HIV-1, the pairwise sequence divergence within an FIV subtype ranged from 2.5 to 15.0%, whereas that between subtypes ranged from 17.8 to 26.2%. However, the high number of synonymous nucleotide changes among FIV V3 to V5 env sequences may also include a significant number of back mutations and suggests that the evolutionary distances among FIV subtypes are underestimated. Although only a few subtype B viruses were available for examination, the pattern of diversity between the FIV A and B subtypes was found to be significantly distinct; subtype B sequences had proportionally fewer mutations that changed amino acids, compared with silent changes, suggesting a more advanced state of adaptation to the host. No similar distinction was evident for HIV-1 subtypes. The diversity of FIV genomes within individual infected cats was found to be as high as 3.7% yet twofold lower than that within HIV-1-infected people over a comparable region of the env gene. Despite these differences, significant parallels between patterns of FIV evolution and HIV-1 evolution exist, indicating that a wide array of potentially divergent virus challenges need to be considered in FIV vaccine and pathogenesis studies.

Adaptation, Biological↗
PubMed2000

Proviral HIV-1 dynamics and evolution in patients receiving efficient long-term antiretroviral combination therapy.

OBJECTIVES: Different experimental approaches have shown that, despite plasma viral loads under the threshold of detection, HIV-1 frequently continues to replicate in patients receiving potent antiretroviral therapy. However, whether this low-grade viral replication is sufficient for the generation of new major quasispecies has not been studied. Thus, in order to evaluate the extent of variation in the major proviral HIV-1 population, we monitored proviral DNA sequences in such patients over a time period of up to 30 months. METHODS: DNA was extracted from peripheral blood mononuclear cells (PBMC) and the V3 region was amplified by nested polymerase chain reaction (PCR) and directly sequenced. Additionally, both HIV-1 RNA and DNA levels and CD4+ T-lymphocyte counts were monitored. RESULTS: Analysing the V3 gene sequences of 17 patients, we observed a sequence evolution in nine patients. Interestingly, the majority of these changes (77%) occurred in the first interval following the initiation of therapy and despite signs of ongoing replication the proviral DNA levels continued to decrease in all patients. CONCLUSIONS: Our data suggest that, although available data report that HIV-1 continues to replicate in patients with undetectable viraemia, the extent of viral replication in many of these patients is not sufficient to result in changes in the major viral population.

Adult↗
PubMed1997

Tempo and mode of nucleotide substitutions in gag and env gene fragments in human immunodeficiency virus type 1 populations with a known transmission history.

The complex evolutionary process of human immunodeficiency virus type 1 (HIV-1) is marked by a high level of genetic variation. It has been shown that the HIV-1 genome is characterized by variable and more constant regions, unequal nucleotide frequencies, and preference for G-to-A substitutions. However, this knowledge has largely been neglected in phylogenetic analyses of HIV-1 nucleotide sequences, even though these analyses are applied to a number of important biological questions. The purpose of this study was to identify a realistic model of HIV-1 evolution and to statistically test if the application of such a model significantly improves the accuracy of phylogenetic analyses. A unique and recently reported HIV-1 transmission cluster consisting of nine infected individuals, for whom the direction and time for each transmission were exactly known, formed the basis for the analyses which were performed under a general model of nucleotide substitution using population sequences from the env V3 and p17gag regions of the HIV-1 genome. Examination of seven different substitution models by maximum-likelihood methods revealed that the fit of the general reversible (REV) model was significantly better than that of simpler models, indicating that it is important to account for the asymmetric substitution pattern of HIV-1 and that the nucleotide substitution rate varied significantly across sites. The shape parameter alpha, which describes the variation across sites by a gamma distribution, was estimated to be 0.38 and 0.25 for env V3 and p17gag, respectively. In env V3, the estimated average transition/transversion rate ratio was 1.42. Thus, the REV model with variable rates across sites (described by a gamma distribution) provides the best description of HIV-1 evolution, whereas simple models are unrealistic and inaccurate. It is likely that the accuracy of phylogenetic studies of HIV-1 and many other viruses would improve substantially by the use of more realistic nucleotide substitution models. This is especially true when attempts are made to estimate the age of distant viral ancestors from contemporary viral sequences.

Base Sequence↗
PubMed1993

[HIV infection among type A and B hemophiliacs].

Evolution of HIV infection was studied in 480 hemophiliacs A and 78 hemophiliacs B treated in the "Centre-West" Region. 23.3% hemophiliacs A and 46.1% hemophiliacs B were contaminated by HIV. In this region, HIV seroprevalence in hemophiliacs A was lower than the prevalence noted at the national level (51.2%); this is certainly due to the use of frozen cryoprecipitates in the treatment of a high number of hemophiliacs A. A higher number of hemophiliacs B developed the disease: 12.5% hemophiliacs A versus 22% hemophiliacs B. Moreover hemophilic B patients had a more rapid evolution towards the disease since 6 out of 14 hemophiliacs A and 7 out of 8 hemophiliacs B with AIDS died. The fact that hemophiliacs B were significantly older than hemophiliacs A might be one of the reasons, but it must be noted that the contamination often occurred earlier in hemophiliacs B and was perhaps more important. The more severe evolution in the hemophiliac B group noted in our region is not found in American studies, which may be due to the different ways of preparing Factor IX concentrates in France and the United States.

Adolescent↗
PubMed1996

Random important alterations in HIV-1 viral quasispecies after antiviral treatment.

The evolution of HIV-1 viral populations was studied in a set of MT-2-co-cultured viruses isolated from five patients at the beginning of treatment with zidovudine and after 11-36 months of drug therapy. We first characterized the HIV-1 pol gene to detect the zidovudine-resistance mutations at codons 215 and 219. To analyse the effect that the selective pressure of zidovudine on pol exerted on other genomic regions, we also studied the env gene. The env gene sequence of virus isolated from one individual was unchanged, whereas three other sample pairs had minor alterations in env. In one individual, we detected a significant change in the env gene sequence, and so performed a clonal analysis on viruses isolated before and after treatment. In this individual, the zidovudine-resistant variant that became predominant in the resistant virus population was an undetected minority variant of the viral population before treatment was initiated. These results indicate that the evolution of quasispecies produced by selective pressure on the pol gene from zidovudine treatment could select, in a random process, important changes in other genomic regions; in particular, we describe alterations in the env gene.

Anti-HIV Agents↗
PubMed2006

Transmitted drug-resistant HIV-1 in primary HIV-1 infection; incidence, evolution and impact on response to antiretroviral therapy.

OBJECTIVES: The aim of the study was to determine the incidence and persistence of transmitted drug-resistant HIV-1 in an incident cohort between 2000 and 2004, and to investigate the impact of transmitted drug-resistant HIV-1 on the response to antiretroviral therapy (ART). METHODS: A prospective, nonrandomized study was carried out on 140 individuals identified with primary HIV-1 infection (PHI). PHI was defined as an HIV-positive antibody test with an HIV antibody-negative result in the prior 6 months (n = 69); positive HIV DNA in the absence of antibody (n = 30); an evolving titre positive HIV antibody test (n = 23), or an incident 'detuned' assay (B clade viruses only) (n = 18). Genotypic resistance testing was performed at baseline, following ART and annually over a 4-year period. RESULTS: The prevalence of transmitted drug-resistant HIV-1 infection between January 2000 and June 2004 was nine in 140 (6.0%) and the annual incidence was stable. Seven of these nine patients had a single point mutation conferring single-class drug resistance and the other two patients had multiple mutations conferring multiclass drug resistance (MDR). In eight of the nine cases, mutations conferring drug resistance persisted for more than 12 months off therapy. In contrast to transmitted MDR HIV-1, the virological response to initial ART and CD4 decline were comparable in those with wild-type virus, virus with 'polymorphisms' (secondary mutations) and virus with single drug-resistance mutations. CONCLUSIONS: The incidence of transmitted drug-resistant HIV remained stable and low over a 4-year period. Although MDR remains rare, its presence significantly affects the response to first-line ART, predisposes towards the accumulation of new resistance mutations and is associated with a more rapid CD4 decline.

Adult↗
PubMed2003

Genetic and biological properties of HIV type 1 isolates prevalent in villagers of the Cameroon equatorial rain forests and grass fields: further evidence of broad HIV type 1 genetic diversity.

To understand the evolution of HIV-1, the genetic and biological characteristics of viruses that infect persons living in regions in which the virus has been evolving for several decades must be studied. Thus, we investigated teh genetic subtypes, coreceptor usage, and syncytium-inducing ability of viruses in 47 HIV-1-infected blood samples from individuals living in rural villages in the equatorial rain forest and grass field regions in Cameroon. Heteroduplex mobility analysis (HMA) of gag (part of p24 and p7) and env (C2V5) or sequence and phylogenetic analysis of gag (part of p24 and p7), pol (protease), and env (C2V5), revealed a broad HIV-1 group M genetic diversity. Subtype analysis revealed genetic evidence of seven subtypes (A, C, D, F, G, H, and J) and three circulating recombinant froms (CRFs) (CRF01_AE, CRF02_AG, and CRF11_cpx). Only 15 (32%) of the 47 samples analyzed revealed a concordant subtype in all three genes (gag, pol, and env), while discordant subtypes and CRFs were identified for the remaining 32 (68%) samples. Two patterns of HIV-1 diversity could be discerned in two provinces. While more concordant subtypes in gag, pol, and env genes were identified in villages of South province (10 of 13, 77%), the HIV-1 diversity in the West province was characterized by intersubtype recombinants (63%). Five new intersubtype recombinants were identified including Agag Jpol Genv, Ggag Upol Aenv, AGgag Jpol Aenv, Agag AGpol Henv, and Cgag AGpol AGenv. All of the 40 viruses tested used the R5 coreceptor, of which four also used the X4 coreceptor. Four viruses were able to induce syncytia in MT-2 cells, however, syncytium induction did not correlate with coreceptor usage. This study further reveals the complexity of HIV-1 infection in rural Cameron and points to the future of the global epidemic, which may be characterized by more genetically diverse viruses.

Cameroon↗
PubMed2004

Intra-host evolution of human immunodeficiency virus type 1 and viral fitness.

RNA viruses are frequently tolerant to high levels of mutagenesis. In contrast, DNA viruses are less errorprone and coevolve along with their specific hosts over long time periods. Although both strategies have been successful, the "RNA-strategy" (directly linked to the pathogenic potential of these agents) most often generates novelty (new variants, new strains, and even new viral pathogens). For several decades, intra-host virus evolution has been considered to be a speculative field, far from the main issues of clinical virology. This concept is now changed, due to the evidence that RNA virus evolution is intimately linked to failures in viral disease control and prevention. Antiviral strategies using single and fixed elements (i.e. treatments using one antiviral compound, immunizations using a single recombinant protein) have been unable to control highly dynamic quasispecies, such as human immunodeficiency virus type I (HIV-1) and hepatitis C virus (HCV). The development of combinatorial treatments in HIV-1 infection and the recognition that vaccines should be multivalent are important steps in adapting disease control strategies to the complexity of viral populations. The present report summarizes the strategies adopted to address HIV-1 evolution and its phenotypic consequences, including changes in susceptibility to antiviral compounds, viral fitness, and pathogenic potential. In particular, it is highlighted that sequence-function analyses of the intra-host HIV-I evolution, including studies of viral fitness, have opened up new perspectives not only to studying the pathogenic mechanisms and the virus-host relationships, but also to designing new strategies for monitoring antiviral therapies.

AIDS Vaccines↗
PubMed2004

Molecular clock-like evolution of human immunodeficiency virus type 1.

The molecular clock hypothesis states that the rate of nucleotide substitution per generation is constant across lineages. If generation times were equal across lineages, samples obtained at the same calendar time would have experienced the same number of generations since their common ancestor. However, if sequences are not derived from contemporaneous samples, differences in the number of generations may be misinterpreted as variation in substitution rates and hence may lead to false rejection of the molecular clock hypothesis. A recent study has called into doubt the validity of clock-like evolution for HIV-1, using molecular sequences derived from noncontemporaneous samples. However, after separating their within-individual data according to sampling time, we found that what appeared to be nonclock-like behavior could be attributed, in most cases, to noncontemporaneous sampling, with contributions also likely to derive from recombination. Natural selection alone did not appear to obscure the clock-like evolution of HIV-1.

Evolution, Molecular↗
PubMed2004

Genotypic and phenotypic correlates of the HIV Type 1 env gene evolution in infected children with discordant response to antiretroviral therapy.

The genotypic-phenotypic correlates of human immunodeficiency virus type 1 (HIV-1) env gene evolution were investigated in samples from eight infected children under antiretroviral therapy (ART) and virological failure. Evolution of the gp120 C2-V5 env sequence was demonstrated in all subjects but one by sequence analysis of the replicating plasma virus collected at baseline and 12-15 months after ART initiation. The analysis of the host's selective pressure showed that in four subjects, the ratio of nonsynonymous to synonymous amino acid substitutions was higher in the V3 sequences than in the C2-V5 region ([K (a)/K (s)](V3)/[K (a)/K (s)](C2V5) >1.0). Interestingly, this feature was observed only in subjects (four of five) showing an increase in T cell receptor rearrangement excision circle (TREC)-bearing cells and in CD4(+) T-lymphocytes despite persistent viremia (discordant therapeutic response) (p = 0.02), thus suggesting that the V3 loop is a target of the immune reconstitution under ART. Using phenotypic analysis of recombinant viruses expressing exogenous V3 sequences, a reverse shift from CXCR4-tropic to CCR5-tropic variants was demonstrated in two of the four subjects, further indicating that the host's selective pressure sharply forces the V3 evolution of replicating variants. The data indicate that a complex HIV-1-host interplay occurs in children receiving antiretroviral treatments and suggest that the recovery of thymic function places a selective constraint on the viral V3 loop.

Anti-Retroviral Agents↗
PubMed2004

Long-term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug-resistant genotypes.

HIV-1 evolution and the possible emergence of mutations associated with resistance to antiretroviral inhibitors have been evaluated in a cohort of sixty-three patients successfully treated with highly active antiretroviral therapy (HAART). The patients under effective HAART were recruited in three different hospitals in Spain, and none of them had been treated (naïve) before entering this study. HIV-1 RNA levels, CD4+, and CD8+ T-cell counts were determined, and nucleotide sequences of proviral regions encoding protease and reverse transcriptase (RT) were obtained for longitudinal blood samples spanning a mean follow-up period of 88 weeks. Phylogenetic reconstructions and calculations of genetic distances among the different sequences of each patient were performed. All except one of the patients under study showed an early and sustained decrease in plasma HIV-1 RNA to levels that were below 200 copies/ml. The plasma viral decline paralleled a significant increase in the CD4+ T-lymphocyte counts. Amino acid sequence analyses revealed the occurrence of mutations associated with antiretroviral resistance in nine patients (14.3%) during HAART treatment, that in some cases could be attributed to excess G to A transitions. In six of the nine patients, the mutations conferred resistance to inhibitors administered in the treatment regime, although the mutations did not result in treatment failure. Sequence comparisons revealed viral evolution during the period of treatment in 47.5% of the patients. The results indicate successful suppression of HIV-1 under HAART for extended time periods, indistinguishable for patients in which evidence of virus evolution could or could not be documented.

Adult↗
PubMed1999

Higher selection pressure from antiretroviral drugs in vivo results in increased evolutionary distance in HIV-1 pol.

We investigated the effect of selection pressures on evolution of HIV-1 pol in 51 patients after switching to a new antiretroviral combination reverse transcriptase (RT) inhibitor therapy. Evolution of the protease (PR) and RT reading frames were analysed separately. Pairwise evolutionary distances (ED) were calculated between sequences from baseline and week 8 and between baseline and week 48 of protocol therapy. ED were calculated for all substitutions and for synonymous and nonsynonymous substitutions separately. At week 8 when HIV RNA reduction (selection pressure) was high, significantly more divergence in pol in both synonymous and nonsynonymous substitutions was found in patients with substantial RNA reduction (strong responders). Separate analyses of PR and RT revealed significantly greater ED in the RT (under selection pressure) of strong compared with nonresponders, whereas divergence between PR genes (not under selection pressure) did not differ in those two groups. Such differential evolution indicates that PR and RT were genetically unlinked and suggests recombination. The rapid increase of ED over the first 8 weeks was followed by only a minimal further rise by week 48, suggesting that selection of preexisting quasispecies accounted for the early changes. A disproportionally high number of synonymous substitutions accounted for the observed divergence and indicated that such genetic changes may not be completely silent.

Anti-HIV Agents↗
PubMed1998

[Evolution of the prevalence of HIV-1 infection in drug addicts in the Community of Madrid (1985-1986)].

BACKGROUND: To evaluate the evolution of the HIV infection in the drug addicts of Madrid. PATIENTS AND METHODS: Data of 2,234 patients that entered for the first time in a Psychiatric Hospital Detoxication Unit of Madrid from October 1985 to december 1996 were recorded. RESULTS: There was a reduction of the percentage of addicts infected by the HIV (of the 66 to 25%), also in the IVDUs men (of the 70 to 37.6%), but not in women. There was an increase in the number of addicts that had never injected drugs (of the 7 to the 45%). CONCLUSIONS: Despite the reduction of HIV infection rate in drugs addicts in Madrid, it remains still very high.

Acquired Immunodeficiency Syndrome↗
PubMed2007

HIV and pharmacogenomics in 2007.

Saye Khoo is Reader in the Department of Pharmacology at the University of Liverpool (UK), having graduated from the University of London in 1985. He is Honorary Consultant in Infectious Diseases, and is lead clinician for the Royal Liverpool University Hospital, and the Mersey, Cheshire & North Wales HIV Managed Care Network. Khoo has also served in the BHIVA Treatment Guidelines Writing committee, PENTA Pharmacology committee, and as an editor for the Journal of Antimicrobial Chemotherapy. Research interests include assessment of intracellular accumulation of HIV drugs, role of drug transporters, evolution of HIV resistance within drug sanctuary sites, drug-drug interactions, therapeutic drug monitoring and pharmacogenomics of HIV therapy. Similar work is also in progress with TB drugs in regard to sterilizing activity.

Anti-HIV Agents↗