Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study

Abstract

Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC) region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662) were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir) are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes) and chromosome 8 (rs2575735; within the Syndecan 2 gene). Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir.

Comparative Analysis of the Capacity of Elite Suppressor CD4 + and CD8 + T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages

“…This idea has long been supported by both functional studies examining the response and quality of ES CD8 ϩ T cells (2, 3, 5, 10, 36-40) and genome-wide association studies identifying major histocompatibility complex class I alleles (such as HLA-B*57 and HLA-B*27) (41)(42)(43)(44)(45)(46). In addition, these protective HLA alleles have been shown to be overrepresented in multiple ES cohorts (5,41,(47)(48)(49)(50)(51)(52).…”

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

“…Genome-wide association studies (GWASs) have shown that variation in HLA class I region has the greatest differential influence on HIV viral load control (17)(18)(19)(20)(21)(22). Delineating the precise "causal" locus/loci, however, is problematic in the rich environment of functionally related, highly polymorphic, and tightly linked disease candidate loci located within the MHC.…”

Human Leukocyte Antigen Variants B*44 and B*57 Are Consistently Favorable during Two Distinct Phases of Primary HIV-1 Infection in Sub-Saharan Africans with Several Viral Subtypes

“…In most studies, a quantitative measure of VL is used without reference to estimated date of infection (EDI), under the assumption that patients are seldom observed during acute-phase (peak) infection and that the early chronic-phase (set-point) VL is usually stable for years in patients with no apparent manifestations of immunodeficiency. Factors known or suspected to influence VL range from viral mutations (changes in replication fitness or switches in coreceptor tropism) (15,28,39,72) to host genes that govern innate and adaptive immune responses (54,75,81,83,84,86).Within the human nuclear genome, human leukocyte antigen (HLA) class I genes are the most convincing (and universally applicable) quantitative trait loci for HIV-1 viremia (14,16,17,66). However, the individual HLA alleles, haplotypes, and supertypes with reported impacts on HIV-1 VL are not always clear because their distribution and patterns of linkage disequilibrium often differ from one population to another (7,53,63).…”