ANALYSIS OF A BIALLELIC POLYMORPHISM IN THE TUMOR-NECROSIS-FACTOR A PROMOTER AND HIV TYPE-1 DISEASE PROGRESSION

The relevance of a TNF-alpha promoter polymorphism, a G-to-A polymorph ic sequence at position-308, was examined to test whether variant alle les of TNF-alpha affect susceptibility to infection with HIV-1 and pro gression to AIDS. Analysis of specimens from cohorts of HIV-1 positive homosexual men demonstrated that 3 of the 32 (9.4%) HIV-1-infected lo ng-term nonprogressors (LTNPs) were homozygous for the uncommon TNF-2 allele compared with 3 of the 196 (1.5%) HIV-1-seronegative blood dono rs and uninfected homosexual men (p < 0.05), There was no difference i n heterozygosity among HIV-1-seropositive or -seronegative groups, alt hough some of the seropositive men heterozygous for the TNF2 genotype were also heterozygous for CCR5 Delta 32. However, no significant asso ciation was found between TNF genotypes and time of survival, CD4 slop es, or viral loads when seroincident (n = 109) and seroprevalent cases (n = 442) from the Chicago MACS were analyzed, Functional analysis of lymphocytes from the seronegative group revealed no difference in end ogenous or mitogen-induced TNF-alpha production, as well as susceptibi lity to in vitro HIV-1 infection between different TNF-genotype donors , These data suggest that TNF genotypes do not play a direct role in H IV-1 disease progression; however, they could potentially be part of a multigenic linkage that may be involved in delaying progression to AI DS.