Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples This information is current as Jianming Tang, Wenshuo Shao, Yun Joo Yoo, Ilene Brill, of September 25, 2021. Joseph Mulenga, Susan Allen, Eric Hunter and Richard A. Kaslow J Immunol 2008; 181:2626-2635; ; doi: 10.4049/jimmunol.181.4.2626 http://www.jimmunol.org/content/181/4/2626 Downloaded from References This article cites 67 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/181/4/2626.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples1 Jianming Tang,2* Wenshuo Shao,† Yun Joo Yoo,3‡ Ilene Brill,† Joseph Mulenga,§ Susan Allen,§¶ Eric Hunter,§ʈ and Richard A. Kaslow2*† Differences in immune control of HIV-1 infection are often attributable to the highly variable HLA class I molecules that present viral epitopes to CTL. In our immunogenetic analyses of 429 HIV-1 discordant Zambian couples (infected index partners paired with cohabiting seronegative partners), several HLA class I variants in index partners were associated with contrasting rates and incidence of HIV-1 transmission within a 12-year study period. In particular, A*3601 on the A*36-Cw*04-B*53 haplotype was the most unfavorable marker of HIV-1 transmission by index partners, while Cw*1801 (primarily on the A*30-Cw*18-B*57 haplo- Downloaded from type) was the most favorable, irrespective of the direction of transmission (male to female or female to male) and other commonly recognized cofactors of infection, including age and GUI. The same HLA markers were further associated with contrasting viral load levels in index partners, but they had no clear impact on HIV-1 acquisition by the seronegative partners. Thus, HLA class I gene products not only mediate HIV-1 pathogenesis and evolution but also influence heterosexual HIV-1 transmission. The Journal of Immunology, 2008, 181: 2626–2635. http://www.jimmunol.org/ s molecules responsible primarily for Ag presentation HIV-1 infection (reviewed in Refs. 13, 14). Regardless of HIV-1 and immune surveillance, HLA products are best known clade (e.g., subtypes A, B, and C), B57 (mostly B5701 and B5703) A for their extensive allelic diversity (1–4), which is con- predominantly and persistently directs CTL recognition of highly con- sidered essential to the constant combat with a wide range of hu- served HIV-1 Gag epitopes (e.g., IW9 and KF11) (8, 15). As the man pathogens (5). Epidemiologic and experimental analyses of infection progresses, viruses with mutations within and around these patients with chronic or terminal HIV-1 infection have revealed epitopes accumulate. Despite diminished immune protection, viremia multiple HLA class I alleles that can differentially regulate viro- often remains low, as viral replication fitness is apparently compro- logic, immunologic, and clinical outcomes, often through their mised. Upon transmission to individuals without B57 and closely re- preferential targeting of conserved or variable HIV epitopes for lated alleles like B5801, viruses with the mutated Gag epitopes usu- by guest on September 25, 2021 CTL responses (6–8). Such CTL responses also lead to predict- ally regain the wild-type sequence (11, 16). In contrast, unfavorable able HIV-1 mutations and immune escape, as documented in pa- alleles like B35 and B53 preferentially respond to Nef epitopes (8); tients from Australia (9, 10), Sub-Saharan Africa (10, 11), and subsequent Nef mutations are typically associated with disease pro- North America (8, 12). gression (12). Thus, heterogeneity in immune control and rate of dis- The profound impact of diverse HLA alleles (designated by four ease progression following HIV-1 infection is to some degree related digits) and allele groups (designated by two digits or serologic spec- to pathways mediated by HLA products. ificities) on HIV-1 evolution and pathogenesis is best illustrated by Favorable HLA factors with a clear impact on HIV-1 viral load B57, which is by far the most favorable HLA factor in the context of directly benefit the infected individual by delaying disease progres- sion (13, 14), in a manner and degree similar to that observed with HIV-specific monotherapy (reviewed in Ref. 17). These HLA factors *Department of Medicine, †Department of Epidemiology, and ‡Department of Bio- may further benefit seronegative individuals who are at high risk of statistics, University of Alabama at Birmingham, Birmingham, AL 35294; §Rwanda/ Zambia HIV-1 Research Group, Lusaka, Zambia; and ¶Department of Global Health acquiring infection because viral load in plasma or genital secretions and ʈVaccine Research Center, Emory University, Atlanta, GA 30322 of a seropositive partner is highly predictive of HIV-1 transmission Received for publication March 7, 2008. Accepted for publication June 10, 2008. potential (18, 19). Our study of HIV-1 discordant couples (infected The costs of publication of this article were defrayed in part by the payment of page index partners paired with cohabiting seronegative partners) from charges. This article must therefore be hereby marked advertisement in accordance Lusaka, Zambia has yielded clear evidence that viral transmission with 18 U.S.C. Section 1734 solely to indicate this fact. from index to seronegative partners can vary according to specific 1 This work was supported in part by National Institute of Allergy and Infectious HLA class I alleles or haplotypes, often as a result of their influences Diseases through grants AI40951 (to S.A.), AI41530 (to J. Michael Kilby), AI41951 (to R.A.K.), AI51173 (to J.T.), and AI64060 (to E.H.). J.T. is the recipient of an on plasma viral load of the index partners. Independent Scientist Award (AI76123) from National Institute of Allergy and In- fectious Diseases. Materials and Methods 2 Address correspondence and reprint requests to Dr. Jianming Tang or Dr. Richard A. Kaslow, Program in Epidemiology of Infection and Immunity, Schools of Medi- Study population and HIV-1 transmission as the primary cine and Public Health, University of Alabama at Birmingham, 1665 University Bou- outcome levard, Birmingham, AL 35294-0022. E-mail address: [email protected] or rkaslow@ uab.edu From 1995 to 2006, HIV-1 discordant Zambian couples were identified and 3 Current address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, To- enrolled continuously by investigators who are now part of the Rwanda/ ronto, Canada. Zambia HIV-1 Research Group in Lusaka, Zambia. Procedures for initial screening, voluntary counseling and testing, as well as prospective (quar- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 terly) medical examination have been described elsewhere (19, 20). As the www.jimmunol.org The Journal of Immunology 2627 tion analysis (Dynal/Invitrogen), automated sequence-specific oligonucle- otide probe hybridization (Innogenetics), and automated sequencing-based typing (Abbott Molecular). These techniques achieved medium- to high- resolution typing of HLA class I alleles in the study population (23–26). Novel alleles and ambiguities were also resolved by confirmatory sequenc- ing-based typing using capillary electrophoresis and the ABI 3130ϫl DNA Analyzer (Applied Biosystems). Occasionally, alleles could not be distin- guished by their exon 2 to exon 3 sequences that encode the peptide- binding groove. In these circumstances, a letter “g” (for group) was added to the most probable allele in assignment and reported as such (e.g., Cw*1701g for alleles Cw*1701, Cw*1702, and Cw*1703) (27). Manual and computational assignment of local and extended HLA haplotypes Common HLA-B (B) and HLA-C (C) haplotypes were initially assigned manually according to known patterns of strong linkage disequilibrium (LD)4 for well-documented and fully resolved alleles observed in African- Americans (28) and for medium-resolution typing results from a native African (Rwandan) population (29). Observation of common B-C haplo- types in homozygous state provided additional assurance of accuracy in manual haplotype assignment. Infrequent or rare haplotypes were inferred after the common haplotypes were assigned. Further evaluation of haplo- Downloaded from types involving alleles from two loci (pairwise) or all three class I loci used the expectation-maximization (EM) algorithm in SAS Genetics (SAS In- FIGURE 1. Classification of 566 Zambian couples (1132 individuals) stitute), with relative LD (D’) and correlation coefficient (r) as key mea- enrolled for longitudinal study from