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Session 51 Poster Session Impact of Host Genetics on Viral Transmission and Disease Progression Session Time: 4:30-6:30 pm Room 4E-F

321-W. The Association of Polymorphisms in HLA Class I and TAP Genes with Resistance to HIV-1 Infection C. Liu1, M. Carrington2, R. A. Kaslow3, C. Rinaldo4, L. Jacobson5, J. Margolick5, J. Phair6, and R. Detels*1 1Univ. of California, Los Angeles; 2NCI, NIH, Frederick, MD; 3Univ. of Alabama, Birmingham; 4Univ. of Pittsburgh, PA; 5Johns Hopkins Univ., Baltimore, MD; and 6Howard Brown Hlth. Ctr., Northwestern Univ. Med. Sch., Chicago, IL Background: Several studies have shown that human leukocyte antigen (HLA)-restricted immune responses are involved in resistance to viral infection. The main objective of this study was to examine relationships of HLA class I and the transporter associated with antigen processing (TAP) genes with resistance to human immunodeficiency virus (HIV)-1 infection. Methods: From the Multicenter AIDS Cohort Study (MACS), 100 persistently seronegative men who had been repeatedly exposed to HIV-1, and 184 infected persons with lower risk were included in this study according to an algorithm based on the number of different insertive anal sexual partners 2.5 years prior to the second semiannual evaluation. HLA class I genes were typed by sequence-specific oligonucleotide (SO) and sequence-specific primer (SSP) methods supplemented by direct sequencing. The TAP genes were typed with sequence-specific oligonucleotide (SSO) and DNA single-strand conformation polymorphism (SSCP) typing methods. Univariate c2 frequency analysis and multiple logistic regression were employed to explore the association between the genetic variants and HIV-1 resistance. Fisher's exact test was used where necessary. Results: A*6802 (Odds Ratio [OR], 7l.63; 95% confidence interval [CI], 0.84-69.17; p-0.05) and B*1302 (OR, 2.92; 95% CI, 1.01-8.45; p-0.04) were found marginally associated with HIV-1 resistance in univariate analysis. None of 9 previously defined HLA class I supertypes was associated with HIV-1 infection. The significant association of the A2/6802 supertype excluding A*0201 (OR, 4.45; 95% CI, 1.33-4.84; p=0.009) was due completely to the effects of the A*0205 subgroup. Alleles in this subgroup share similar structure in the binding groove and preferentially bind some peptides with common anchor residues. Susceptibility to HIV-1 infection was strongly associated with the recently identified Px subfamily (OR, 0.29; 95% CI, 0.08-0.99; p=0.04) of B*35, which suggests that different binding preference at the C terminus may influence the binding capacity or that TAP gene products selectively transport peptides with proline at position 2. As in a previous study, the TAP2.3 variant (exon 11,665 ala) was associated with HIV-1 resistance (OR, 2.26; 95% CI, 1.35-3.79; p=0.002), perhaps because of its greater efficiency in transporting peptides eliciting a strong protective immune response although linkage disequilibrium is also possible. In multivariate analysis no single HLA allele association was statistically significant, but the TAP2.3 variant (OR, 2.10; 95% CI, 1.20-3.67; p=0.009) and the A*0205 subgroup (OR, 5.75; 95% CI, 1.38-23.86; p=0.02) remained significantly associated with HIV-1 resistance. Conclusions: Some HLA class I alleles and the TAP2.3 variant are closely associated with HIV-1 resistance. Functional mechanisms are considered.

©2002 9th Conference on Retroviruses and Opportunistic Infections