Goulder, P. J. R. & Watkins, D. I. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nature Rev. Immunol. 8, 619-630

Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK.
Nature Reviews Immunology (Impact Factor: 34.99). 07/2008; 8(8):619-30. DOI: 10.1038/nri2357
Source: PubMed


The recent failure of the T-cell-based HIV vaccine trial led by Merck & Co., Inc. prompts the urgent need to refocus on the question of which T-cell responses are required to control HIV replication. The well-described association between the expression of particular MHC class I molecules and successful containment of HIV or, in the macaque model, SIV replication provide a valuable starting point from which to evaluate more precisely what might constitute effective CD8(+) T-cell responses. Here, we review recent studies of T-cell-mediated control of HIV and SIV infection, and offer insight for the design of a successful T-cell-based HIV vaccine in the future.

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    • "In a cross-sectional study from South Africa, viral loads varied by a factor of more than 10,000, but the factors underlying this heterogeneity are not completely clear [115]. Some factors have been recognized; for example, HLA-B57 and HLA-B27 genotypes have been associated with better viral control, and this leads one to expect that individuals with these HLA types are, on average, less infectious than others [116]. However, there is also within-person variation, and individuals may temporarily shed more infectious virions than usual [117]. "
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    ABSTRACT: Several countries with generalized, high-prevalence HIV epidemics, mostly in sub-Saharan Africa, have experienced rapid declines in transmission. These HIV epidemics, often with rapid onsets, have generally been attributed to a combination of factors related to high-risk sexual behavior. The subsequent declines in these countries began prior to widespread therapy or implementation of any other major biomedical prevention. This change has been construed as evidence of behavior change, often on the basis of mathematical models, but direct evidence for behavior changes that would explain these declines is limited. Here, we look at the structure of current models and argue that the common "fixed risk per sexual contact" assumption favors the conclusion of substantial behavior changes. We argue that this assumption ignores reported non-linearities between exposure and risk. Taking this into account, we propose that some of the decline in HIV transmission may be part of the natural dynamics of the epidemic, and that several factors that have traditionally been ignored by modelers for lack of precise quantitative estimates may well hold the key to understanding epidemiologic trends.
    Full-text · Article · Mar 2014 · PLoS Computational Biology
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    • "The strength of peptide binding to MHC class I is a key determinant in CTL epitope immunogenicity ( Goulder and Watkins , 2008 ) . We therefore identified known HLA A * 0201 - and B * 0702 - restricted HIV - 1 CTL epitopes in autologous sequences from subject 8 based on previously established immunologic activity ( Yusim , 2004 ) . "
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    ABSTRACT: It is unclear if HIV-1 variants lose the ability to prime naïve CD8+ cytotoxic T lymphocytes (CTL) during progressive, untreated infection. We conducted a comprehensive longitudinal analysis of viral evolution and its impact on primary and memory CD8+ T cell responses pre-seroconversion (SC), post-SC, and during combination antiretroviral therapy (cART). Memory T cell responses targeting autologous virus variants reached a nadir by 8 years post-SC with development of AIDS, followed by a transient enhancement of anti-HIV-1 CTL responses upon initiation of cART. We show broad and high magnitude primary T cell responses to late variants in pre-SC T cells, comparable to primary anti-HIV-1 responses induced in T cells from uninfected persons. Despite evolutionary changes, CD8+ T cells could still be primed to HIV-1 variants. Hence, vaccination against late, mutated epitopes could be successful in enhancing primary reactivity of T cells for control of the residual reservoir of HIV-1 during cART.
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    • "Nef has a complex role in HIV pathogenicity via a number of mechanisms, including down-regulation of host CD4 and MHC cell surface expression, modulation of T cell function, and altering of macrophage signaling [2–4]. Nef is among the most diverse HIV proteins [5]. The greatest sequence variability is focused in the amino- (N-) and carboxy- (C-) terminal regions, while the central portion of the protein is substantially more conserved [6–8]. "
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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.
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