Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes.

Department of Microbiology, SC-42, University of Washington School of Medicine, Seattle, WA 98195-8070, USA.
Journal of Virology (Impact Factor: 4.65). 05/2011; 85(15):7523-34. DOI: 10.1128/JVI.02697-10
Source: PubMed

ABSTRACT HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.

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    ABSTRACT: The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL escape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN-γ ELISpot and longitudinal HIV-1 gag, pol, and nef sequence data were used to study the timing and prevalence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero respectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two years.
    PLoS Genetics 02/2015; 11(2):e1004914. DOI:10.1371/journal.pgen.1004914 · 8.17 Impact Factor
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    ABSTRACT: The evolution rates of the hepatitis B virus (HBV) estimated using contemporary sequences are 102-104 times faster than those derived from archaeological and genetic evidence. This discrepancy makes the origin of HBV and time scale of its spread, both of which are critical for studying the burden of HBV pathogenicity, remains largely unresolved. To evaluate whether the dual demands (i.e., adaptation within hosts and colonization between hosts) of the viral life cycle affect this conundrum, the HBV quasispecies dynamics within and among hosts from a family consisting of a grandmother, her 5 children, and her 2 granddaughters, all of whom presumably acquired chronic HBV through mother-to-infant transmission, were examined by PCR cloning and next generation sequencing methods. We found that evolutionary rate of HBV between hosts was considerably lower than that of within hosts. Moreover, the between-host substitution rates of the HBV decreased as transmission numbers between individual increased. Both observations were primarily due to changes at nonsynonymous rather than synonymous sites. There were significantly more multiple substitutions than expected under random mutation process and 97% of substitutions were changed from common to rare amino acid residues in the database. Continual switching between colonization and adaptation resulted in the rapid accumulation of mutations at a limited number of positions, which quickly became saturated, whereas substitutions at the remaining regions occurred at a much slower rate. Our study may help to explain the time-dependent HBV substitution rates reported in the literature and provide new insights into the origin of the virus. IMPORTANCE: It is known that the estimated hepatitis B virus (HBV) substitution rate is time-dependent, but the reason behind is still elusive. We hypothesize that, owing to their small genome size, the transmission between hosts and adaptation within hosts must exhibit high levels of fitness tradeoffs for the viruses. By studying the HBV quasispecies dynamics from a chain of sequentially infected transmissions within a family, we found HBV substitution rate between patients to be negatively correlated with the number of transmissions. Continual switching between hosts resulted in the rapid accumulation of mutations at a limited number of genomic sites, which quickly became saturated in the short-term. Nevertheless, substitutions at the remaining regions occurred at a much slower rate. Therefore, the HBV substitution rate decreased as the divergence time increased.
    Journal of Virology 11/2014; DOI:10.1128/JVI.03131-14 · 4.65 Impact Factor
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    ABSTRACT: Background The reproducible nature of HIV-1 escape from HLA-restricted CD8+ T-cell responses allows the identification of HLA-associated viral polymorphisms ¿at the population level¿ ¿ that is, via analysis of cross-sectional, linked HLA/HIV-1 genotypes by statistical association. However, elucidating their timing of selection traditionally requires detailed longitudinal studies, which are challenging to undertake on a large scale. We investigate whether the extent and relative timecourse of immune-driven HIV adaptation can be inferred via comparative cross-sectional analysis of independent early and chronic infection cohorts.ResultsSimilarly-powered datasets of linked HLA/HIV-1 genotypes from individuals with early (median¿<¿3 months) and chronic untreated HIV-1 subtype B infection, matched for size (N¿>¿200/dataset), HLA class I and HIV-1 Gag/Pol/Nef diversity, were established. These datasets were first used to define a list of 162 known HLA-associated polymorphisms detectable at the population level in cohorts of the present size and host/viral genetic composition. Of these 162 known HLA-associated polymorphisms, 15% (occurring at 14 Gag, Pol and Nef codons) were already detectable via statistical association in the early infection dataset at p¿¿¿0.01 (q¿<¿0.2) ¿ identifying them as the most consistently rapidly escaping sites in HIV-1. Among these were known rapidly-escaping sites (e.g. B*57-Gag-T242N) and others not previously appreciated to be reproducibly rapidly selected (e.g. A*31:01-associated adaptations at Gag codons 397, 401 and 403). Escape prevalence in early infection correlated strongly with first-year escape rates (Pearson¿s R¿=¿0.68, p¿=¿0.0001), supporting cross-sectional parameters as reliable indicators of longitudinally-derived measures. Comparative analysis of early and chronic datasets revealed that, on average, the prevalence of HLA-associated polymorphisms more than doubles between these two infection stages in persons harboring the relevant HLA (p¿<¿0.0001, consistent with frequent and reproducible escape), but remains relatively stable in persons lacking the HLA (p¿=¿0.15, consistent with slow reversion). Published HLA-specific Hazard Ratios for progression to AIDS correlated positively with average escape prevalence in early infection (Pearson¿s R¿=¿0.53, p¿=¿0.028), consistent with high early within-host HIV-1 adaptation (via rapid escape and/or frequent polymorphism transmission) as a correlate of progression.Conclusion Cross-sectional host/viral genotype datasets represent an underutilized resource to identify reproducible early pathways of HIV-1 adaptation and identify correlates of protective immunity.
    Retrovirology 08/2014; 11(1):64. DOI:10.1186/PREACCEPT-8878001841312932 · 4.77 Impact Factor


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Jun 5, 2014