Analyses of host genes that confer immune resistance against human immunodeficiency virus type-1 infection in HIV-1-exposed but uninfected individuals in the overseas cohorts

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Despite multiple and repeated exprosures to HIV-1, some individuals possess no detectable HIV genome and show T-cell memory responses to the viral antigens. HIV-1-reactive mucosal IgA detected in such uninfected individuals suggests their possible immune resistance against HIV. We tested if the above HIV-1-exprosed but uninfected status was associated with genetic markers other than a homozygous deletion of the CCR5 gene.Based on our mapping in chromosoma 15 of a gene controlling the production of neutralizing antibodies in a mouse retrovirus infection, we genotyped 42 HIV-1-exposed but uninfected Italians at polymorphic loci in the syntenic segment of human chromosome 22, and compared them with 49 HIV-1-infected and 47 uninfected healthy control individuals by a closed testing procedure. A significant association was found between chromosome 22q12-13 genotypes and a putative dominant locus conferring anti-HIV-1 immune responses in the exposed but uninfected individuals. Distributions of linkage disequilibrium across chromosome 22 also differed between the exposed but uninfected and two other phenotypic groups.We next stimulated the peripheral blood mononuclear cells from HIV-1-exposed but uninfected and HIV-1-infected individuals with a mixture of HIV-1 gag and env antigens, and compared the expression of all the genes and open reading frames located in the above candidate region using a DNA microarray technique. Significant induction of several genes at 6 hours after the antigenic stimulation was observed only in the exposed but uninfected individuals. Further linkage of a single nucleotide polymorphism located in one candidate gene with the genotype of the D22S423 marker was observed only in the exposed but uninfected individuals. These data indicated the presence of a new genetic factor associated with the HIV-1-exposed but uninfected status.