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Articles by Philip J . R. Goulder
Total Records ( 2 ) for Philip J . R. Goulder
  Christine M. Rousseau , Marcus G. Daniels , Jonathan M. Carlson , Carl Kadie , Hayley Crawford , Andrew Prendergast , Philippa Matthews , Rebecca Payne , Morgane Rolland , Dana N. Raugi , Brandon S. Maust , Gerald H. Learn , David C. Nickle , Hoosen Coovadia , Thumbi Ndung’u , Nicole Frahm , hristian Brander , Bruce D. Walker , Philip J . R. Goulder , Tanmoy Bhattacharya , David E . Heckerman , Bette T. Korber and James I. Mullins
  Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL) recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads (q < 0.2 [where q is the expected false-discovery rate]) in individuals with the corresponding HLA alleles. The ratio of susceptible to resistant residues among those without the corresponding HLA alleles varied in the order Vpr > Gag > Rev > Pol > Nef > Vif > Tat > Env > Vpu (Fisher’s exact test; P ≤ 0.0009 for each comparison), suggesting the same ranking of fitness costs by genes associated with CTL escape. Significantly more HLA-B (χ2; P = 3.59 x 10–5) and HLA-C (χ2; P = 4.71 x 10–6) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.
  Philippa C. Matthews , Andrew Prendergast , Alasdair Leslie , Hayley Crawford , Rebecca Payne , Christine Rousseau , Morgane Rolland , Isobella Honeyborne , Jonathan Carlson , Carl Kadie , Christian Brander , Karen Bishop , Nonkululeko Mlotshwa , James I . Mullins , Hoosen Coovadia , Thumbi Ndung’u , Bruce D. Walker , David Heckerman and Philip J . R. Goulder
  Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8+ T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert posttransmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = –0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = –0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.
 
 
 
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