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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    ABSTRACT: A 3739 nucleotide fragment of Infectious Hypodermal and Hematopoietic Necrosis Virus (IHHNV) from Brazil was amplified and sequenced. This fragment contains the entire coding sequences of viral proteins, the full 3' untranslated region (3'UTR) and a partial sequence of 5' untranslated region (5'UTR). The genome organization of IHHNV revealed the three typical major coding domains: a left ORF1 of 2001bp that codes NS1, a left ORF2 (NS2) of 1091bp that codes NS2 and a right ORF3 of 990bp that codes VP. The nucleotide and amino acid sequences of the three viral proteins were compared with the putative amino acid sequences of viruses reported from different regions. Comparisons among genomes from different geographic regions reveal 31 nucleotide regions that are 100% similar, distributed throughout the genome. An analysis of secondary structure of the UTR regions, revealed regions with high probability to form hairpins, that may be involved in mechanisms of viral replication. Additionally a maximum likelihood analysis indicates that Brazilian IHHNV belongs to lineage III in the infectious IHHNV group, and is clustered with IHHNV isolates from Hawaii, China, Taiwan, Vietnam and South Korea. A new nested PCR targeting conserved nucleotide regions is proposed to detect IHHNV.
    Virus Research 05/2014; 189. DOI:10.1016/j.virusres.2014.05.008 · 2.32 Impact Factor
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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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    ABSTRACT: In HIV-1 infection, plasma viral load (VL) has dual implications for pathogenesis and public health. Based on well-known patterns of HIV-1 evolution and immune escape, we hypothesized that VL is an evolving quantitative trait that depends heavily on duration of infection (DOI), demographic features, human leukocyte antigen (HLA) genotypes and viral characteristics. Prospective data from 421 African seroconverters with at least four eligible visits did show relatively steady VL beyond 3 months of untreated infection, but host and viral factors independently associated with cross-sectional and longitudinal VL often varied by analytical approaches and sliding time windows. Specifically, the effects of age, HLA-B⁎53 and infecting HIV-1 subtypes (A1, C and others) on VL were either sporadic or highly sensitive to time windows. These observations were strengthened by the addition of 111 seroconverters with 2–3 eligible VL results, suggesting that DOI should be a critical parameter in epidemiological and clinical studies.
    Virology 01/2014; 449:254–262. DOI:10.1016/j.virol.2013.11.024 · 3.32 Impact Factor
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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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    ABSTRACT: Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.
    PLoS ONE 09/2013; 8(9):e73117. DOI:10.1371/journal.pone.0073117 · 3.23 Impact Factor
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