Reduced mortality and CD4 cell loss among carriers of the interleukin-10 -1082G allele in a Zimbabwean cohort of HIV-1-infected adults.
OBJECTIVE
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.
Erikstrup
Christian
C
Centre for Inflammation and Metabolism, Denmark. erikstrup@dadlnet.dk
Kallestrup
Per
P
Zinyama-Gutsire
Rutendo B
RB
Gomo
Exnevia
E
Butterworth
Anthony E
AE
Pedersen
Bente K
BK
Ostrowski
Sisse R
SR
Gerstoft
Jan
J
Ullum
Henrik
H
D000328:Adult; D000483:Alleles; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D003906:Developing Countries; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000401:mortality*; D015497:HIV-1; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014779:Virus Replication; D015030:Zimbabwe
D015415:Biomarkers; D016209:Interleukin-8; D012367:RNA, Viral; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10