Genome-Wide Analyses Reveal Gene Influence on HIV Disease Progression and HIV-1C Acquisition in Southern Africa

Abstract

Sub-Saharan Africans infected with HIV-1C make up the largest AIDS patient population in the world and exhibit large heterogeneity in disease progression before initiating antiretroviral therapy. To identify host variants associated with HIV disease progression, we performed genome-wide association studies on a total of 556 treatment-naive HIV-infected individuals in Botswana. We characterized the pattern of HIV disease progression using a novel functional principal component analysis, which can better capture longitudinal CD4 and viral load (VL) trajectories. Two single-nucleotide polymorphisms (SNPs) near HCG22 (chr6, peak variant rs2535307, combined p = 3.72 × 10, minor allele as risky allele) and CCNG1 (chr5, peak variant kgp22385164, combined p = 1.88 × 10, minor allele as risky allele) were significantly associated with CD4 and VL dynamics. Inspection of SNPs in these gene regions in a third Botswana cohort (using GWATCH) also revealed a strong association of HCG22 with HIV-1C acquisition, suggesting that this region is associated with infection as well as disease progression. Our study uncovered two genetic regions that are significant and have specific effects on HIV-1C acquisition or progression in sub-Saharan Africans, and the result suggested new potential targets for AIDS prevention and treatment. In addition, our results also indicate the possibility of using genetic markers as HIV disease progression indicators in sub-Saharan Africans to prioritize fast progressors for antiretroviral treatment.

Population Structure and Implications on the Genetic Architecture of HIV-1 Phenotypes Within Southern Africa

“…A validation test was done in data from three independent American cohorts, and no significant association was observed around the two genes ( HCG22 and CCNG1 ). SNPs that were found to associate with HIV infection and progression in previous studies did not appear in the top 100,000 p-values in this study (Xie et al, 2017).…”

“…GWAS of HIV-1 have also been performed in other populations, African Americans, Hispanics, Chinese, and Africans (Pelak et al, 2010; Pereyra et al, 2010; Petrovski et al, 2011; Wei et al, 2015; Xie et al, 2017). Pereyra et al identified an intergenic SNP rs2523590 in Hispanics, Europeans, and Americans.…”

“…The most recent HIV-1 GWAS was also conducted in an African (Botswana) population (Xie et al, 2017). This is the first GWAS to reveal significant variants associated with HIV-1 acquisition and progression in an African population.…”

“…The minor alleles of both SNPs led to lower CD4 T-cell counts and high viral loads. HCG22 was associated with progression and acquisition of HIV1-C, while CCNG1 was associated with progression only in the Botswana cohort [ Table 2 (Xie et al, 2017)]. A validation test was done in data from three independent American cohorts, and no significant association was observed around the two genes ( HCG22 and CCNG1 ).…”

The CCR5-Delta32 genetic polymorphism and HIV-1 infection susceptibility: a meta-analysis

“…Host genetic diversity has an important role in either disease susceptibility or resistance [ 4 , 5 ]. However, the positive role of different genes in HIV/AIDS progression has still remained controversial [ 6 , 7 ].…”