Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10

IL10 is a powerful TH-2 cell cytokine produced by lymphoid cells that limit s HIV-1 replication in vivo, ostensibly by inhibiting macrophage/monocyte a nd T-cell lymphocyte replication and secretion of inflammatory cytokines (I L1, TNF alpha, IL6, IL8, and IL12). A genetic epidemiological scan of patie nts enrolled in AIDS cohorts for candidate gene-linked short tandem repeat polymorphisms revealed significant genotype associations for HIV-1 infectio n and progression to AIDS with markers adjacent to and tracking (by linkage disequilibrium) common single nucleotide polymorphic variants in the IL10 promoter region. Individuals carrying the IL10-5'-592A (IL10-5'A) promoter allele possibly were at increased risk for HIV-1 infection, and once infect ed they progressed to AIDS more rapidly than homozygotes for the alternativ e IL10-5'-592 C/C (IL10-+/+) genotype. particularly in the later stages of HIV-1 infection. An estimated 25-30% of long-term nonprogressors (who avoid clinical AIDS for 10 or more years after HIV-1 infection) can be attribute d to their IL10-+/+ promoter genotype. Alternative IL10 promoter alleles ar e functionally distinct in relative IL10 production, in retention of an avi an erythroblastosis virus transcription factor recognition sequence and in binding to specific putative nuclear transcription factors, suggesting a po tential mechanism whereby IL10-5'A down-regulation of inhibitory IL10 facil itates HIV-1 replication in vivo, accelerating the onset of AIDS.