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: 4.44). 05/2011; 85(15):7523-34. DOI: 10.1128/JVI.02697-10
Source: PubMed


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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Available from: john paul mcnevin, Sep 29, 2015
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    • "Lastly, we wished to identify adaptation-related features that discriminate protective from non-protective HLA alleles, defined here as their published hazard ratios for progression to AIDS [HR-AIDS] in natural history studies [36]. Although the timecourse of viral escape is influenced by complex factors including epitope immunodominance hierarchies, strength of selection, mutational/fitness constraints and transmitted virus characteristics [17,19,34,37-40], we reasoned that HLA alleles that restrict polymorphisms that are already highly prevalent in early infection (due to rapid escape and/or frequent transmission) would be generally unfavorable for HIV-1 control. Thus, for all HLA alleles for which ≥2 adapted polymorphisms were investigated in the present study (N = 17 alleles total), we computed their mean “percentage escaped” in early infection. "
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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 · 4.19 Impact Factor
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    • "Table 2 shows the analysis of one of the amplicons (gag3, 383 bp with primers trimmed). ICC reduced the number of variable sites by an average of 84%, and the overall trend was as expected for early HIV infection, with a slightly higher level of diversity early and then increasing diversity through time (Herbeck et al., 2011). "
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    ABSTRACT: Pyrosequencing technology provides an important new approach to more extensively characterize diverse sequence populations and detect low frequency variants. However, the promise of this technology has been difficult to realize, as careful correction of sequencing errors is crucial to distinguish rare variants (∼1%) in an infected host with high sensitivity and specificity. We developed a new approach, referred to as Indel and Carryforward Correction, or ICC, to cluster sequences without substitutions and locally correct only indel and carryforward sequencing errors within clusters to ensure that no rare variants are lost. ICC performs sequence clustering in the order of (a) homopolymer indel patterns only, (b) indel patterns only, and (c) carryforward errors only, without the requirement of a distance cut-off value. Overall, ICC removed 93%-95% of sequencing errors found in control data sets. On pyrosequencing data from a PCR fragment derived from 15 HIV-1 plasmid clones mixed at various frequencies as low as 0.1%, ICC achieved the highest sensitivity and similar specificity compared to other commonly used error correction and variant calling algorithms.Availability and implementation: Source code is freely available for download at It is implemented in Perl and supported on Linux, Mac OS X and MS Windows. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Bioinformatics 07/2013; 29(19). DOI:10.1093/bioinformatics/btt434 · 4.98 Impact Factor
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    • "For the WH level, the database contained one adequate dataset, originating from a US patient [11,12]. Four additional datasets [13], also from US patients, could be analysed but they were all from acute infections (they spanned at most over 11 months) and had lower genome-wide coverage. For the BH data, many of the sequences we used originated from a study conducted in Boston [14]. "
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    ABSTRACT: Background HIV evolves rapidly at the epidemiological level but also at the within-host level. The virus’ within-host evolutionary rates have been argued to be much higher than its between-host evolutionary rates. However, this conclusion relies on analyses of a short portion of the virus envelope gene. Here, we study in detail these evolutionary rates across the HIV genome. Results We build phylogenies using a relaxed molecular clock assumption to estimate evolutionary rates in different regions of the HIV genome. We find that these rates vary strongly across the genome, with higher rates in the envelope gene (env). Within-host evolutionary rates are consistently higher than between-host rates throughout the HIV genome. This difference is significantly more pronounced in env. Finally, we find weak differences between overlapping and non-overlapping regions. Conclusions We provide a genome-wide overview of the differences in the HIV rates of molecular evolution at the within- and between-host levels. Contrary to hepatitis C virus, where differences are only located in the envelope gene, within-host evolutionary rates are higher than between-host evolutionary rates across the whole HIV genome. This supports the hypothesis that HIV strains that are less adapted to the host have an advantage during transmission. The most likely mechanism for this is storage and then preferential transmission of viruses in latent T-cells. These results shed a new light on the role of the transmission bottleneck in the evolutionary dynamics of HIV.
    Retrovirology 05/2013; 10(1):49. DOI:10.1186/1742-4690-10-49 · 4.19 Impact Factor
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