| Abstract: | Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.Since the first report of this virus in 1986, HIV-2 remains largely confined to West Africa (11). It shares between 30 and 60% nucleotide and amino acid homology with HIV-1 but differs greatly in pathogenicity and transmissibility (20). Studies on HIV-2 patients across West Africa have shown that some people remain uninfected despite repeated exposure (36), and a substantial proportion of infected people remain relatively healthy for a very long time with low plasma viral load and normal CD4+ T-cell counts, a characteristic of long-term nonprogressors (LTNPs) infected with HIV-1 (37). This is perhaps a reflection of an effective immune response mounted against the virus, including a vigorous CD8+ T-cell response (28), maintenance of HIV-specific CD4+ T-cell function (15), and the presence of a strong neutralizing antibody response in many subjects (4), features that are highly desirable for a successful HIV-1 vaccine. Thus, HIV-2 disease course provides a natural model for investigating mechanisms that control HIV infection, and a better understanding of these mechanisms might inform new strategies for HIV prevention and treatment.HLA class I molecules present antigenic epitopes to cytotoxic T cells and are central to the acquired immune response. A number of associations between HLA class I alleles and HIV disease outcomes have been reported (10), the most consistent being B*57 and B*27, which show strong protection across studies, and certain subtypes of B*35, which associate with more rapid progression (19). While several mother-infant studies have implicated sharing of certain HLA alleles in transmission of the virus from mother to infant (29, 30), there is no convincing data that particular HLA class I alleles protect against HIV infection in general.HLA class I allotypes also serve as ligands for killer cell immunoglobulin-like receptors (KIRs), which modulate natural killer (NK) cell function. KIRs are structurally similar to one another and can be divided into activating and inhibitory receptors. NK cells are key components of the innate immune system and constantly survey host cell surfaces for appropriate levels of HLA class I molecules through a network of NK cell receptors, including KIRs (26). Upon engagement with their ligand, inhibitory KIR suppress NK cell activity, but if the ligand is missing or has been downregulated on target cells, the threshold for NK cell activation is lowered, thus allowing for activation signals to dominate (23).HLA and KIR genes are found on chromosomes 6 and 19, respectively, so they segregate independently. As such, the genes/alleles for the corresponding receptor-ligand pair must be present to confer functionality, whereas presence of one without the other results in a null phenotype. A number of HLA and KIR gene products either individually or collectively has been implicated in the control of HIV-1 (9), but nothing is known of their role in HIV-2.Epidemiological data from Caio and other cohorts in West Africa (3, 39) indicate that HIV-2 infection in a substantial proportion of infected individuals is compatible with normal survival and without signs of immunodeficiency, suggesting distinct viral pathogenic mechanisms and protective host factors against HIV-2 relative to HIV-1. Here, we determined the HLA class I and KIR gene profiles of the Caio population (>95% Manjako) from Guinea-Bissau and investigated their effects on susceptibility to HIV-2 infection and disease progression. |
