Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency Virus Type 1 Infection in Native Africans

Department of Epidemiology, University of Alabama at Birmingham, AL 35294, USA.
Journal of Virology (Impact Factor: 4.44). 06/2006; 80(12):6056-60. DOI: 10.1128/JVI.02119-05
Source: PubMed


Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties.
We examined alleles of the HLA-B58 supertype (B58s) in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-seropositive
Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular
methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate
for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In
HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802
with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable
responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact
on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against
HIV/AIDS in every population.

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    • "However, only a third of HLA matched hosts mount an epitope-specific response [41]; and the six major MHC determinants of HIV-1 protection in Caucasians [42] lacked protective associations in African cohorts [26]. It is also unclear why the widely protective HLA B*5801 [18] [43] [44] lacked protection in clade A-infected Rwandans [45]. Others also demonstrated higher A163X frequencies among clade A subjects [27]. "
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    ABSTRACT: We evaluated relationships between critical Gag T-cell escape mutations and concomitant T-cell responses to determine whether HLA-restricted Gag mutations that confer protection, occur at similar rates in a population infected with mixed HIV-1 clades A1 and D viruses. Assessment of Gag selective pressure, and adaptive T-cell functions to KAFSPEVIPMF (KF11), ISPRTLNAW (ISW9) and TSTLQEQIGW (TW10) Gag epitopes were combined with host HLA to assess correlations with rates of critical epitope escape mutations in clades A1- (n=23) and D- (n=21) infected, untreated subjects. Infecting clades and selection pressure were determined from the gag sequences. Overall, Gag escape mutations A163X in KF11 were detected in 61% (14/23) A1- infected compared to 5% (1/21) in D-infected subjects (p=0.00015). Gag mutations I147X in the ISW9 epitope were seen in 43%: (10/23) clade A compared to 5%: (1/21) clade D infected subjects, p=0.007, Fisher's Exact test. Both mutations were more frequent in clade A1 infection. Frequencies of the measured epitope-specific T-cell responses were comparable across clades. Peptide binding affinities for the restricting HLA alleles did not differ across clades. Overall, selection pressure on the Gag protein was significantly greater in clade A than in clade D sequences. These findings imply that HIV-1 vaccine strategies designed to target structurally constrained T-cell epitopes may be further challenged by clade-driven outcomes in specific HLA-restricted Gag epitopes. Equally, the data are line with slower HIV-1 disease progression in clade A infection; and raise hope that increased selective pressure on Gag may be protective irrespective of host HLA alleles. Copyright © 2015. Published by Elsevier Ltd.
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    • "A follow up study from the same group showed that peptide presentation properties of particular B*35 subtypes explain much of this association [38]. The dominance of HLA-B in the control of HIV-1 infection is supported by several studies which associated HLA-B*57, B*5801 and B*27 with slower disease progression rates (time to AIDS) and strong virologic (viral load) and immunologic control (CD4 count) [39-48], while B*35, B*5802 and B*18 were associated with ineffective control of viral replication and rapid progression to AIDS [37,43,44,47,49,50]. In addition, a significantly greater number of CD8+ T cell responses are HLA-B restricted, compared to HLA-A and -C. "
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    ABSTRACT: The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins.
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    • "Their allelic variants have been associated with various outcomes in the natural course of HIV-1 infection, including viremia and disease progression (time to manifest immunodeficiency after infection) [9], [10], [11], [12], [13], [14], [15]. Favorable HLA alleles like HLA-B*57 and B*27 have strong and durable impact on both early and late outcomes including set-point VL [6], [16], [17], [18], [19], [20], [21], [22], and they appear to reduce or delay viral transmission by suppressing viremia in an infected potential transmitter (e.g., a sexual partner) [6],[21]. In contrast, evidence that HLA variants influence acquisition in HESNs is less convincing; associations reported for various class I alleles (A*23, A*68:02, A*74 and B*18) have been less consistent in studies of mother-infant pairs [23], [24], commercial sex workers [25], [26], [27] and other high-risk groups [28]. "
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