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. 2015 Mar 17;10(3):e0119886.
doi: 10.1371/journal.pone.0119886. eCollection 2015.

High frequency of transmitted HIV-1 Gag HLA class I-driven immune escape variants but minimal immune selection over the first year of clade C infection

Kamini Gounder  1 , Nagavelli Padayachi  1 , Jaclyn K Mann  1 , Mopo Radebe  1 , Mammekwa Mokgoro  1 , Mary van der Stok  1 , Lungile Mkhize  1 , Zenele Mncube  1 , Manjeetha Jaggernath  1 , Tarylee Reddy  2 , Bruce D Walker  3 , Thumbi Ndung'u  4
Affiliations

High frequency of transmitted HIV-1 Gag HLA class I-driven immune escape variants but minimal immune selection over the first year of clade C infection

Kamini Gounder et al. PLoS One. .

Abstract

In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Neighbour joining trees and Highlighter plots of longitudinal HIV-1 gag diversity from recently infected individuals.
(A) Neighbour-joining phylogenetic tree of longitudinal (from 14 days to 1 year post infection) gag sequences from 22 recently infected HIV-1 participants and consensus subtype C reference sequence from the HIV database (www.hiv.lanl.gov). Gag sequences from the earliest time point are shown in red circles and in blue circles at 1 year post infection. (*) denotes samples sequenced later than 14 days post infection (AS3–0513, AS2–1037, AS2–0802, AS2–0945 and AS1–0876 were sequenced at 28, 34, 35, 46 and 101 days post-infection respectively). (B) Participant AS3_0513 with a highly homogeneous gag sequence population at screening (∼28 days post infection) displaying limited structure on a tree (left) and little or no nucleotide changes from the intrapatient consensus at 28 days post infection. (C) Participant AS3_0767 infected with four closely related gag populations based on the clustering of sequences. Heterogeneous, multiple variant gag sequences population at 14 days post infection visually represented by a phylogenetic tree (left) with extensive branching topology and Highlighter plots (right) with diverse pattern of nucleotide base mutations compared to consensus. Nucleotide polymorphisms are indicated by a colored tic mark (thymine in red, adenine in green, cytosine in blue and guanine in orange) and deletions are shown by gray tics in the Highlighter plots. (★) denotes the consensus sequence obtained from the earliest time point sequences.
Fig 2
Fig 2. Multiple variant transmission and intrapatient diversity results in higher viral load set point.
(A) Association of single versus multivariant transmission sequences versus viral load set point in individuals sequenced at the earliest time point (Student’s T test). (B) Significantly higher intrapatient diversity in individuals infected with multiple variants (Student’s T test). (C) Significantly higher intrapatient diversity within gag over one year of infection (Paired T test). (D) Intrapatient diversity of HIV-1 Gag at 14 days post infection correlation with viral load set point. Significant correlations of intrapatient diversity at 1 year versus viral load set point (E) and viral load at one year (F). (*) denotes statistical significant difference.
Fig 3
Fig 3. Percentage distribution of consensus and variant Gag sequence patterns in individuals at the earliest time point.
(A) Percentage of consensus, variant and known CTL variants within host specific epitopes from HLA class I alleles at the earliest time of infection. Distribution of consensus, variant and percentage of variants as CTL variants within host-specific HLA restricted Gag epitopes in individuals possessing the selecting HLA-A (B), HLA-B (C) and HLA-C (D) alleles and those individuals who do not possess the selecting HLA allele at the earliest time point. (E) Overall distribution of adapted and non-adapted HLA-associated escape mutations within individuals that select and do not select for Gag polymorphisms at the earliest time of infection. Distribution of adapted (F) and non-adapted (G) mutations expressing HLA-A, HLA-B and HLA-C alleles that select and do not select for Gag polymorphisms at the earliest time of infection.
Fig 4
Fig 4. Percentage distribution of consensus and variant Gag sequence patterns in individuals over one year of HIV-1 infection.
(A) Percentage of consensus, variant and known CTL variants within host specific epitopes from HLA class I alleles at one year post infection. Distribution of consensus, variant and percentage of variants as CTL variants within host-specific HLA restricted Gag epitopes in individuals possessing the selecting HLA-A (B), HLA-B (C) and HLA-C (D) allele and those individuals who do not possess the selecting HLA allele over one year of infection. (E) Overall distribution of adapted and non-adapted HLA-associated escape mutations within individuals that select and do not select for Gag polymorphisms by one year post infection. Distribution of adapted (F) and non-adapted (G) mutations expressing HLA-A, HLA-B and HLA-C alleles that select and do not select for Gag polymorphisms one year post infection.
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