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PubMed2003

Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients.

The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

Adult↗

PubMed1999

Search for the mechanism of genetic variation in the pro gene of human immunodeficiency virus.

To study the mechanism of evolution of the human immunodeficiency virus (HIV) protease gene (pro), we analyzed a database of 213 pro sequences isolated from 11 HIV type 1-infected patients who had not been treated with protease inhibitors. Variation in pro is restricted to rare variable bases which are highly diverse and differ in location among individuals; an average variable base appears in about 16% of individuals. The average intrapatient distance per individual variable site, 27%, is similar for synonymous and nonsynonymous sites, although synonymous sites are twice as abundant. The latter observation excludes selection for diversity as an important, permanently acting factor in the evolution of pro and leaves purifying selection as the only kind of selection. Based on this, we developed a model of evolution, both within individuals and along the transmission chain, which explains variable sites as slightly deleterious mutants slowly reverting to the better-fit variant during individual infection. In the case of a single-source transmission, genetic bottlenecks at the moment of transmission effectively suppress selection, allowing mutants to accumulate along the transmission chain to high levels. However, even very rare coinfections from independent sources are, as we show, able to counteract the bottleneck effect. Therefore, there are two possible explanations for the high mutant frequency. First, the frequency of coinfection in the natural host population may be quite low. Alternatively, a strong variation of the best-adapted sequence between individuals could be caused by a combination of an immune response present in early infection and coselection.

Base Sequence↗

PubMed1995

Estimating the sexual mixing patterns in the general population from those in people acquiring gonorrhoea infection: theoretical foundation and empirical findings.

STUDY OBJECTIVES: To describe mathematically the relationship between patterns of sexual mixing in the general population and those of people with gonorrhoea infection, and hence to estimate the sexual mixing matrix for the general population. DESIGN: Integration of data describing sexual behaviour in the general population, with data describing sexual behaviour and mixing among individuals infected with gonorrhoea. Use of these data in a simple mathematical model of the transmission dynamics of gonorrhoea infection. SETTING: The general population of London and a genitourinary medicine (GUM) clinic in west London. PARTICIPANT: These comprised 1520 men and women living in London who were randomly selected for the national survey of sexual attitudes and lifestyles and 2414 heterosexual men and women who presented to the GUM clinic with gonorrhoea. MAIN RESULTS: The relationship between sexual mixing among people with gonorrhoea and sexual mixing in the general population is derived mathematically. An empirical estimate of the sexual mixing matrix for the general population is presented. The results provide tentative evidence that individuals with high rates of acquisition of sexual partners preferentially select other individuals with high rates as partners (assortative mixing). CONCLUSIONS: Reliable estimates of sexual mixing have been shown to be important for understanding the evolution of the epidemics of HIV infection and other sexually transmitted diseases. The possibility of estimating patterns of sexual mixing in the general population from information routinely collected in gonorrhoea contact tracing programmes is demonstrated. Furthermore, the approach we describe could, in principle, be used to estimate the same patterns of mixing, using contact tracing data for other sexually transmitted diseases, thus providing a way of validating our results.

Adolescent↗

PubMed1998

Biological basis of the HLA-B8,DR3-associated progression of acquired immune deficiency syndrome.

The factors influencing the evolution of human immunodeficiency virus (HIV) infection are not fully known, but the host genotype undoubtedly plays a role in determining the outcome of the disease by affecting the immune response to HIV. The role of the host human leukocyte antigen (HLA) genotype in the regulation of susceptibility to HIV infection and expression has been studied extensively in different major risk groups. Certain HLA alleles and haplotypes, being associated with aberrant immune responses independently from HIV infection, have been reported to facilitate the rapid progression of disorders related to HIV infection. Particularly, the association of rapid acquired immunodeficiency syndrome (AIDS) progression with genes from the HLA-B8,DR3 haplotype has been reported by different research groups. It is well known that this haplotype is associated in all Caucasian populations with a wide variety of diseases with autoimmune features and in healthy subjects with a number of immune system dysfunctions, as a reduced production of T helper (Th)1 type cytokine. HIV infection may act on this genetic background triggering immunopathogenetic mechanisms leading to AIDS with a dominant Th2 profile as a common feature.

Acquired Immunodeficiency Syndrome↗

PubMed1992

[Infection by human herpesvirus type 6: epidemiology, immunopathology and clinical implications].

The human herpesvirus type 6 has been discovered recently and is the object of numerous investigations. Even though, its morphology is very close to the cytomegalovirus, its epidemiologic, immunopathologic and clinic characteristics are similar to the Epstein-Barr virus. Like the latter, HHV-6 persists latent in the host during all his live, frequently relapsed and is ubiquitous. Exanthema subitum in children and mononucleosis-like syndrome in adults have been attributed to acute HHV-6 infection. Under certain conditions, the development of chronic fatigue syndrome, some lymphoproliferative disorders and, perhaps, others diseases can be influenced by the persistent activity of this infection furthermore, HHV-6 can be a cofactor in infection with HIV and provokes a faster evolution and more severe illness.

Herpesviridae Infections↗

PubMed2003

Lack of persistent drug-resistant mutations evaluated within and between treatment interruptions in chronically HIV-1-infected patients.

OBJECTIVE: To determine the effect of treatment interruptions (TI) on the evolution and persistence of drug-resistant viruses in chronically HIV-1-infected suppressed patients. METHODS: The emergence of viral resistance to combination antiretroviral therapy was monitored in 11 suppressed chronically HIV-1-infected patients undergoing from one up to four sequential TI (a total of 25 TI), by genotyping of the virus for known mutations in the genes for protease and reverse transcriptase. Resistance assays were performed at the first viral rebound > 100 copies/ml. RESULTS: All subjects achieved resuppression of HIV-1 under the same antiretroviral therapy, regardless of the number of TI. Five of eleven patients showed no development of resistance. In the remaining six patients, the following patterns of mutations associated with viral resistance were found: one mutation (K70R), which was observed in one patient during the 1st TI and persisted during follow-up; two mutations (L90M, M184V), which were observed in four patients during the 1st TI and were intermittently present or lost following extended TI, treatment reinitiation and/or during subsequent TI; and evolution of two mutations (M184V, K219E) observed in two patients. These two mutations were not present during the 1st TI and were subsequently lost following therapy reinitiation or during the next TI. CONCLUSIONS: Detection of drug resistance during TI by virus genotyping assays does not predict failure to resuppress after antiretroviral therapy reinitiation nor persistence of a resistant viral population during extended interruptions or subsequent TI.

Adult↗

PubMed2003

Monophyletic clade of HIV-1 subtype B in Korea: evolutionary pressure or single introduction?

We have previously shown that many of the nef sequences from Korean HIV-1 subtype B carriers were grouped together in phylogenetic tree analyses. To determine whether this pattern was originated from either a single HIV-1-infected person or some biological pressure which directs the HIV-1 genomic mutation by the Korean specific immunological characters, we analyzed nef sequences from HIV-1-infected individuals with different time intervals. Thirty-two out of 46 analyzed patients formed a Korean monophyletic (KM) clade with 93% bootstrapping value. Eighteen patients' nef sequences were analyzed 1-9 years after first analysis. None of the patients shifted their clade from the first clustered clade (KM or non-KM), and all of the re-analyzed isolates were clustered close to the first analyzed clade. Isolates of the KM dade and non-KM clade in nef analysis showed the same pattern as in env analysis. Phylogenetic clustering evidences from both nef and C2/V3 trees strongly support the idea that introduction of the KM clade in subtype B strains originated from a common source. Thus, treatment and development of an AIDS vaccine may be somewhat easier than in other countries with multiple strains of HIV-1.

Biological Evolution↗

PubMed1997

Long-term evolution of the 5'UTR and a region of NS4 containing a CTL epitope of hepatitis C virus in two haemophilic patients.

Haemophilic patients exposed to unsterilized clotting factor concentrates prior to 1985 have become infected with hepatitis C virus (HCV). We have studied the sequence evolution of the 5'UTR and a region of NS4 over 12 years in one human immunodeficiency virus (HIV) positive haemophilic patient and 14 years for one HIV negative haemophilic patient. One sample each year from the date of HCV infection to 1994 was analysed for genotype, virus load and nucleotide sequence of the two genetic loci. Both patients were infected with HCV genotype 1 throughout the study period. The virus load profiles were similar except that the profile for the HIV infected patient was displaced 4 years earlier relative to the other patient. Mean divergence of the quasispecies at both the 5'UTR and NS4 loci was higher in the HIV coinfected patient. Phylogenetic analysis indicated that evolution of the 5'UTR was host independent, whereas the NS4 region containing a CD8 restricted CTL epitope evolved in a host specific fashion.

Amino Acid Sequence↗

PubMed2005

Evidence for heterogeneous selective pressures in the evolution of the env gene in different human immunodeficiency virus type 1 subtypes.

Recent studies have demonstrated the emergence of human immunodeficiency virus type 1 (HIV-1) subtypes with various levels of fitness. Using heterogeneous maximum-likelihood models of adaptive evolution implemented in the PAML software package, with env sequences representing each HIV-1 group M subtype, we examined the various intersubtype selective pressures operating across the env gene. We found heterogeneity of evolutionary mechanisms between the different subtypes with a category of amino acid sites observed that had undergone positive selection for subtypes C, F1, and G, while these sites had undergone purifying selection in all other subtypes. Also, amino acid sites within subtypes A and K that had undergone purifying selection were observed, while these sites had undergone positive selection in all other subtypes. The presence of such sites indicates heterogeneity of selective pressures within HIV-1 group M subtype evolution that may account for the various levels of fitness of the subtypes.

Amino Acid Sequence↗

PubMed2000

Evolutionary dynamics of HTLV-I.

Using mathematical models to describe the in vivo dynamics of HTLV-I infection, an explanation is offered for the slow rate of evolution of HTLV-I relative to HIV-1. In agreement with experimental findings, it is assumed that cell activation is required for successful replication in T helper cells and that HTLV-I induces a significant degree of bystander activation. It is found that the rate of evolution of HTLV-I is limited by the restricted availability of activated uninfected T cells, both at high and low proviral loads. This limits the within-host sequence diversity of HTLV-I and may therefore account for the slow rate of evolution of the virus in the population. Specific differences in the in vivo dynamics of HTLV-I and HIV-1 are identified which may account for the discrepancy in the rate of evolution of these two retroviruses.

Evolution, Molecular↗

PubMed1999

Roles of p53 and caspases in the induction of cell cycle arrest and apoptosis by HIV-1 vpr.

The vpr gene from the human immunodeficiency virus type-1 (HIV-1) encodes a 14-kDa protein that prevents cell proliferation by causing a block in the G(2) phase of the cell cycle. This cellular function of vpr is conserved in evolution because other primate lentiviruses, including HIV-2, SIV(mac), and SIV(agm) encode related genes that also induce G(2) arrest. After G(2) arrest, cells expressing vpr undergo apoptosis. The signaling pathways that result in vpr-induced cell cycle arrest and apoptosis have yet to be determined. The p53 tumor suppressor protein is involved in signaling pathways leading to cell cycle arrest and apoptosis in a variety of cell types. In this work, we examine the potential role of p53 in mediating cell cycle block and/or apoptosis by HIV-1 vpr and demonstrate that both phenomena occur independently of the presence and function of p53. Caspases are common mediators of apoptosis. We examined the potential role of caspases in mediating vpr-induced apoptosis by treating vpr-expressing cells with Boc-D-FMK, a broad spectrum, irreversible inhibitor of the caspase family. Boc-D-FMK significantly reduced the numbers of apoptotic cells induced by vpr. Therefore, we conclude that vpr-induced apoptosis is effected via the activation of caspases.

Amino Acid Chloromethyl Ketones↗

PubMed1994

[Human immunodeficiency virus type 2 infection in 2 seamen of the northwest of Spain].

The first two cases of HIV-2 infection in autoctonous Spanish subjects are presented. Two sailors (62 and 42 years of age) of Galician origin who travelled to east African countries are reported. The epidemiologic, clinico-evolutive characteristics--with manifestations similar to HIV-1 infection (oral candidiasis and villous leukoplasia)--, and therapeutic response to zidovudine are described. The risk of HIV-2 infection in sailors travelling to Africa and the absence of opportunistic infections in a period of at least 6 to 11 years following infection despite CD4+ lymphocytes being under 0.200 x 10(9)/l, are of note.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Lost in translation: implications of HIV-1 codon usage for immune escape and drug resistance.

Synonymous nucleotide substitutions in protein-coding sequences are often regarded as evolutionarily neutral and not subject to selective pressure. However, synonymous codons can sometimes lead to different patterns of amino acid substitution by single nucleotide changes. Based on the deconstruction of the standard genetic code, we propose the term 'quasi-synonymous' to describe codons that specify the same amino acid, but lie on different mutational pathways, and we show that in at least one rapidly evolving organism, HIV-1, quasi-synonymy plays a role in its evolution. We present concrete examples that demonstrate the relevance of codon usage in the development of antiretroviral-drug resistance. In the case of the host immune response, the data indicates that viral evasion is achieved through use of codons that lie on the direct path to escape mutants, and equally, permit rapid reversion to wild-type in the absence of these selective pressures. Quasi-synonymy conditions HIV-1 and, potentially, other rapidly evolving organisms in their exploration of the mutational space.

Anti-HIV Agents↗

PubMed1997

Evolution of the human immunodeficiency virus type 1 subtype-specific V3 domain is confined to a sequence space with a fixed distance to the subtype consensus.

Human immunodeficiency virus type 1 (HIV-1) strains can be separated into genetic subtypes based on phylogenetic analysis of the envelope gene. Once it had been shown that population-wide intrasubtype genetic variation of HIV-1 strains increases in the course of the AIDS epidemic, it remained uncertain whether HIV-1 subtypes are phenotypic entities spreading as distinct virus populations. To examine this, we applied Eigen's concepts of sequence geometry and fitness topography to the analysis of intrasubtype evolution of the gp120 V3 domain of HIV-1 subtypes A, B, C, and D in the course of the global AIDS epidemic. We observed that despite the high evolution rate of HIV-1, the nonsynonymous distances to the subtype consensus of sequences obtained early in the epidemic are similar to those obtained more than 10 years later, in contrast to the synonymous distances, which increased steadily over time. For HIV-1 subtype B, we observed that the evolution rate of the individual sequences is independent of their distance from the subtype B consensus, but for the individual sequences most distant from the consensus evolution away from the consensus is constrained. As a result, individual HIV-1 genomes fluctuate within a sequence space with fixed distance to the subtype consensus. Our findings suggest that the evolution of the V3 domain of HIV-1 subtypes A, B, C, and D is confined to an area in sequence space within a fixed distance to the consensus of a respective subtype. This in turn indicates that each HIV-1 subtype is a distinct viral quasispecies that is well adapted to the present environment, able to maintain its identity in the V3 region over time, and unlikely to merge during progression of the AIDS epidemic.

Consensus Sequence↗

PubMed2004

Frequent human leukocyte antigen class I alleles are associated with higher viral load among HIV type 1 seroconverters in Thailand.

The loss of viral control by the host may be due to the evolution of viruses with mutations that limit presentation by human leukocyte antigen (HLA) to cytotoxic T cells. The authors hypothesized that the consequence of such evolution might be that persons with common HLA class I alleles would be less able to control viremia, on average, than would those with rare alleles. HLA class I typing was completed for 128 injection drug users who seroconverted in a prospective cohort study in Bangkok, Thailand. Logistic regression was used to model viral load (greater than or equal to the median) at 9 and 12 months after seroconversion with an HLA score that profiled the relative prevalence of each individual's alleles. At 12 months after seroconversion, injection drug users with the most common HLA alleles (highest quartile HLA score) had an almost 4-fold increased risk for higher viral load (> or = 32,055 copies/mL) than injection drug users with less common HLA alleles (adjusted odds ratio, 3.92; 95% confidence interval, 1.3-11.8). These findings support the importance of frequency-dependent effects of host genes on HIV type 1 evolution in different populations and suggest that HLA-driven viral evolution critically influences control of viremia in early HIV type 1 infection.

Alleles↗

PubMed2001

Predicting the unpredictable: transmission of drug-resistant HIV.

We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is high, and predict it will continue to rise. In contrast, we calculate that transmission of resistance is currently low, and predict it will remain low. We show that the epidemic of resistance is being generated mainly by the conversion of drug-sensitive cases to drug-resistant cases, and not by the transmission of resistant strains. We also show that transmission of resistant strains has not increased the overall number of new HIV infections. Our results indicate that transmission of resistant strains is, and will remain, a relatively minor public health problem.

Anti-HIV Agents↗

PubMed2000

Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria.

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost in the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these "costs of resistance" in Escherichia coli, HIV, and Salmonella typhimurium found that evolution in the absence of these drugs commonly results in the ascent of mutations that ameliorate these costs, rather than higher-fitness, drug-sensitive revertants. To ascertain the conditions under which this compensatory evolution, rather than reversion, will occur, we did computer simulations, in vitro experiments, and DNA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutants of E. coli with and without mutations that compensate for the fitness costs of these ribosomal protein mutations. The results of our investigation support the hypothesis that in these experiments, the ascent of intermediate-fitness compensatory mutants, rather than high-fitness revertants, can be attributed to higher rates of compensatory mutations relative to that of reversion and to the numerical bottlenecks associated with serial passage. We argue that these bottlenecks are intrinsic to the population dynamics of parasitic and commensal microbes and discuss the implications of these results to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.

Adaptation, Biological↗

PubMed2004

Semen characteristics in human immunodeficiency virus (HIV)- and hepatitis C (HCV)-seropositive males: predictors of the success of viral removal after sperm washing.

BACKGROUND: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-seropositive males can now father children safely, avoiding transmission risks to the mother and the children using sperm washing and nested PCR (nPCR) techniques. Nevertheless, we still lack enough data to determine the reasons why approximately 10% of the performed sperm washes remain positive, thus forcing the repetition of the treatment. Semen quality in infected males is also essential to these procedures. We aimed to determine the predictive value of the semen parameters, sperm washing procedure and the infection status for the post-wash viral positivity, as well as the correlation between the semen and the disease features. METHODS: Semen characteristics were evaluated in 136 samples provided from 125 males. We also included a control group of 125 males matched by age and length of sexual abstinence. At the time of semen retrieval, 70 of them were infected with HIV (45 also with HCV, 64.3%), and 55 of them with HCV alone. nPCR for viral detection was performed in each sample. RESULTS: Thirteen out of 136 (9.5%) of the samples were positive for one or more viral detections (HIV RNA, HIV DNA and HCV RNA, when needed). From a total of 240 nPCR viral analyses, 16 were positive (6.6%). None of the seminal parameters were adequate to predict post-wash results, nor was a positive result dependent on the volumes used in the semen wash. A positive correlation was found between post-wash progressive motility and CD4 blood levels, as well as a negative correlation between progressive motility and time of evolution of the disease in HIV-infected males. CONCLUSIONS: Semen analysis, according to the World Health Organization criteria, of HIV- and HCV-affected patients showed no differences from that of non-infected males. Moreover, low CD4 blood levels, and a long evolution of the disease do not negatively affect sperm motility.

Anti-Retroviral Agents↗