Protective HLA Class I Alleles That Restrict Acute-Phase CD8+ T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
Journal of Virology (Impact Factor: 4.44). 12/2008; 83(4):1845-55. DOI: 10.1128/JVI.01061-08
Source: PubMed


The control of human immunodeficiency virus type 1 (HIV-1) associated with particular HLA class I alleles suggests that some CD8(+) T-cell responses may be more effective than others at containing HIV-1. Unfortunately, substantial diversities in the breadth, magnitude, and function of these responses have impaired our ability to identify responses most critical to this control. It has been proposed that CD8 responses targeting conserved regions of the virus may be particularly effective, since the development of cytotoxic T-lymphocyte (CTL) escape mutations in these regions may significantly impair viral replication. To address this hypothesis at the population level, we derived near-full-length viral genomes from 98 chronically infected individuals and identified a total of 76 HLA class I-associated mutations across the genome, reflective of CD8 responses capable of selecting for sequence evolution. The majority of HLA-associated mutations were found in p24 Gag, Pol, and Nef. Reversion of HLA-associated mutations in the absence of the selecting HLA allele was also commonly observed, suggesting an impact of most CTL escape mutations on viral replication. Although no correlations were observed between the number or location of HLA-associated mutations and protective HLA alleles, limiting the analysis to mutations selected by acute-phase immunodominant responses revealed a strong positive correlation between mutations at conserved residues and protective HLA alleles. These data suggest that control of HIV-1 may be associated with acute-phase CD8 responses capable of selecting for viral escape mutations in highly conserved regions of the virus, supporting the inclusion of these regions in the design of an effective vaccine.

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Available from: Christian Brander, Sep 12, 2014
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    • "The 162 nt fragment belonging to 5 UTR which was not sequenced in this study is represented by a square with dotted line. A search of nucleotide conserved regions in IHHNV genome was performed in order to identify possible sites of genomic stability, which are often associated with viral infection and replication processes in different viruses (Wang et al., 2009; Kraft et al., 2013; Pollom et al., 2013). These regions are also ideal to PCR targeting especially in cases such as IHHNV which has a large number of variants. "
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    • "HLA allelic products contribute to immune control of viral infection through both innate and adaptive immune pathways (Carrington et al., 2008; Merino et al., 2012, 2013; Stewart et al., 2005). Alleles with early influences on HIV-1 infection tend to impose a strong selection pressure for viral immune escape mutations—a phenomenon that has been repeatedly examined in individuals with HLA-B n 57 and related alleles (Bansal et al., 2007; Crawford et al., 2009; Leslie et al., 2004; Novitsky et al., 2010; Wang et al., 2009). The unfavorable effect of HLA-B n 18 on VL started early and remained stable (Fig. 1), which may translate to a durable impact on HIV-1 pathogenesis. "
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    • "and multiple copies of Nef are produced early in the HIV life cycle [11,12]. Nef is the most targeted protein in acute infection [13–15], accounting for 50% to 90% of CD8+ T cell responses in acutely infected subjects [16,17], as well as having the most CD8+ T cell responses and the highest magnitude IFN-gamma responses in chronic infection [7]. "
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