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. 2008 Jan 9;3(1):e1424.
doi: 10.1371/journal.pone.0001424.

Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads

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Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads

Morgane Rolland et al. PLoS One. .

Abstract

Background: HLA class-I alleles differ in their ability to control HIV replication through cell-mediated immune responses. No consistent associations have been found between the breadth of Cytotoxic T Lymphocytes (CTL) responses and the control of HIV-1, and it is unknown whether the size or distribution of the viral proteome-wide epitope repertoire, i.e., the intrinsic ability to present fewer, more or specific viral epitopes, could affect clinical markers of disease progression.

Methodology/principal findings: We used an epitope prediction model to identify all epitope motifs in a set of 302 HIV-1 full-length proteomes according to each individual's HLA (Human Leukocyte Antigen) genotype. The epitope repertoire, i.e., the number of predicted epitopes per HIV-1 proteome, varied considerably between HLA alleles and thus among individual proteomes. In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire. Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads.

Conclusions/significance: This comprehensive analysis puts forth the epitope repertoire as a mechanistic component of the multi-faceted HIV-specific CTL response. The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag.

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Conflict of interest statement

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

Figures

Figure 1
Figure 1. HIV-1 epitope repertoires and clinical data.
Putative epitopes were identified in silico within full-length autologous HIV-1 proteomes and combined with previously described optimally defined CTL epitopes found in the LANL and IEDB databases. (A) and (B) respectively show the log viral loads and the CD4 counts plotted as a function of the number of predicted HIV-1 epitopes identified per proteome for the individuals with CD4 counts above 400 (n = 81). (C) Shows the number of predicted HIV-1 epitopes for individuals belonging to the highest (mean = 65) and lowest (mean = 76) viremia quartile. (D) Shows the average viral loads of individuals presenting a specific allele as a function of the average number of HIV-1 predicted epitopes for that allele (only alleles presented by at least 3 individuals in the South-African cohort were included).
Figure 2
Figure 2. Distribution of epitopes by HLA alleles and by protein.
Distribution of epitopes among HIV-1 proteins for HLA alleles associated with lowest/highest viral loads. The ratio of predicted epitopes predicted for each protein corresponded to the number of epitope-fulfilling motifs identified in each protein over the total number of epitopes identified for the whole proteome. (A) Shows the distribution of epitopes for “good” alleles, i.e., those associated with the lowest viral loads in the cohort (lowest quartile: VL<125,437; mean = 65,384; median = 58,229). (B) Shows the epitope distribution for “bad” alleles, those associated with the highest viral loads in the cohort (highest quartile: VL>320,643; mean = 971,587; median = 531,208). For each allele belonging to a quartile, average values per allele were calculated based on the viral loads of HLA-matched individuals). (C) Illustrates the percentage of epitopes restricted by “good” and “bad” HLA alleles for each protein.

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