Host genetic predispositions to HIV/AIDS in the AIDS link to intravenous experience (ALIVE) cohort

Chemokines and their receptors are immunological co-factors necessary for HIV-1 binding and entry of the cell. This study evaluated genetic variants in 5 candidate genes (CCR5, CCR5 promoter, CCR2, SDF-1 and RANTES) on initial HIV-1 plasma RNA levels among seroincident individuals in the AIDS Link to Intravenous Experience (ALIVE) cohort. Additionally, we evaluated a novel polymorphism in the secondary co-receptor gene, CXCR6, for its effects on Pneumocystis carinii pneumonia (PCP) infection and HIV/AIDS disease progression among seroincident and seroprevalent individuals in the ALIVE cohort.; We first examined initial HIV-1 plasma RNA within the first 2 years of seroconversion by genetic variants in 5 candidate chemokine or chemokine receptor genes. CCR5-Δ32, CCR2-V64I and SDF-1-3 ′A each had low allele frequencies in this African-American cohort and did not have a statistically significant contribution to HIV-1 plasma RNA variation. CCR5 promoter haplotype P3/P3 and diplotype D/D showed marginally significant effects on initial HIV-1 plasma RNA. The RANTES haplotype, R1 (no genetic variants) was significantly associated with decreased initial HIV-1 plasma RNA by 0.51 log₁₀ units. Our analysis was consistent with previous studies that suggest genetic variants in the RANTES gene downregulate RANTES and appear to increase the initial HIV-1 plasma RNA levels.; We then examined the effects of a novel polymorphism in a secondary co-receptor CXCR6 for its effect on HIV/AIDS disease progression with specific attention to PCP. Using Cox proportional hazard models the CXCR6 E3K variant was associated with decreased risk of AIDS-related death after primary infection with PCP (Relative Hazard = 0.18, CI: 0.05, 0.56). The relative risk of a PCP mediated AIDS-related death for those with the CXCR6 -3K/3K genotype was half the risk of those who carried at least one CXCR6-3E allele. The CXCR6 E3K variant exhibited the same protective trend but was not statistically significant for a decreased risk of death after AIDS-1987, AIDS-1993 and CD4 counts <200. These observations suggest the CXCR6 protective effect may predominantly influence progression from PCP to death by altering mechanisms related to PCP recovery.