Centre for Inflammation and Metabolism, Denmark. erikstrup@dadlnet.dk
OBJECTIVES: To evaluate the effect on HIV progression of single nucleotide polymorphisms in promoters of the genes for tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 and known to influence cytokine production. METHODS: Survival was documented for 4.3 years after baseline for 198 HIV-1-infected and 180 HIV-uninfected individuals from the Mupfure Schistosomiasis and HIV Cohort in rural Zimbabwe. Polymorphisms determined were -592C>A and -1082A>G for IL-10 and -238G>A and -308G>A for TNF-alpha. CD4 cell counts, plasma HIV RNA, soluble TNF receptor II (sTNF-rII), IL-8 and IL-10 were also measured. RESULTS: Mortality was lower in carriers of the IL-10 -1082G high-producer allele (hazard ratio, 0.47; P < 0.01). CD4 cell count decrease in participants reporting for the follow-up at 3 years was attenuated in carriers of this allele (P < 0.01). In univariate analysis, plasma IL-10, IL-8, and sTNF-rII correlated negatively with CD4 cell count, positively with HIV RNA, and higher levels predicted mortality. In multivariate analysis only sTNF-rII was an independent predictor of HIV progression markers and mortality. Indeed, sTNF-rII predicted mortality (P < 0.01) at a level of significance comparable to HIV RNA (P < 0.01) and CD4 cell count (P < 0.05). CONCLUSIONS: In carriers of IL-10 -1082G, an allele linked to increased IL-10 production, survival was doubled and CD4 cell decrease was attenuated compared with noncarriers. Only sTNF-rII and not plasma IL-10 was an independent predictor of HIV progression markers and mortality. This study supports immune activation as a driving force in HIV pathogenesis and indicates a protective role of IL-10 -1082G that should be evaluated in other cohorts.