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Background:  There are individuals who show strong HIV-1 antigen-specific T-cell responses and HIV-1 reactive mucosal IgA production despite the absence of a detectable HIV genome. However, attempts to associate the exposed but uninfected status with a known genetic polymorphism have been unsuccessful.

Methods:  Based on the mapping in chromosome 15 of a gene controlling the production of neutralizing antibodies in a mouse model of retrovirus infection, we genotyped 42 uninfected Italians (ESN) at synthetic polymorphic loci on human chromosome 22, and compared them with HIV-1- infected and uninfected healthy control individuals.

Results:  Objective statistic analyses using a closed testing procedure revealed:  a disruption of linkage disequilibrium across chromosome 22 at 22q13.1 observed only in the ESN group, suggesting a breaking point; and significant association between chromosome 22q13.1 genotypes and a putative dominant locus conferring anti-HIV-1 immune responses in ESN. In the attempt to identify this protective gene, we investigated by RT-REALTIME PCR the levels of expression and the potential stimulators of APOBEC3G and APOBEC3F, endogenous inhibitor of HIV-1 replication, located on human chromosome 22. Results showed that IFN-γ, but not IL-2, stimulation significantly up-regulated APOBEC3G and APOBEC3F independently of IL-15 and that APOBEC3F, but not APOBEC3G, expression was augmented by HIV infection. Even more important, we observed that both basal and IFN-γ-induced expression of APOBEC3G and APOBEC3F was significantly enhanced in ESN compared with HIV patients and healthy controls.

Conclusions:  These findings, besides clarifying the mechanisms regulating the synthesis of APOBEC, indicate the presence of a distinctive genetic background for the HIV-1 ESN and allow us to formulate the hypothesis that high levels of APOBEC3G and APOBEC3F could be associated with resistance to retroviral infections in humans.

Keywords: genetics; apobec; exposed uninfected