RESUMO
IMPORTANCE: It has been previously shown that genetic variants near CHD1L on chromosome 1 are associated with reduced HIV VL in African populations. However, the impact of these variants on viral diversity and how they restrict viral replication are unknown. We report on a regional association analysis in a South African population and show evidence of selective pressure by variants near CHD1L on HIV RT and gag. Our findings provide further insight into how genetic variability at this locus contributes to host control of HIV in a South African population.
Assuntos
DNA Helicases , Proteínas de Ligação a DNA , Loci Gênicos , Variação Genética , Infecções por HIV , HIV-1 , Humanos , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , África do Sul , Carga Viral/genética , Replicação Viral , Transcriptase Reversa do HIV/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismoRESUMO
HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.
Assuntos
DNA Helicases , Proteínas de Ligação a DNA , Variação Genética , Infecções por HIV , HIV-1 , Carga Viral , Humanos , Linhagem Celular , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Infecções por HIV/genética , HIV-1/crescimento & desenvolvimento , HIV-1/fisiologia , Carga Viral/genética , África , Cromossomos Humanos Par 1/genética , Alelos , RNA Longo não Codificante/genética , Replicação ViralRESUMO
Biological sex and host genetics influence HIV pathogenesis. Females have a higher likelihood of spontaneous viral control and lower set point viral load (spVL). No prior studies have assessed sex-specific genetics of HIV. To address this, we performed a sex-stratified genome-wide association study using data from the ICGH. Although it is the largest collection of genomic data in HIV, this multiethnic sample of 9,705 people is 81.3% male. We sought to identify sex-specific genetic variants and genes associated with HIV spVL and control. We confirmed associations in the HLA and CCR5 regions in males and HLA in females. Gene-based analyses detected associations between HIV spVL and PET100, PCP2, XAB2, and STXBP2 only in males. We detected variants with a significant sex-differential effect on spVL in SDC3 and PUM1 (rs10914268) and PSORS1C2 (rs1265159) and on HIV control in SUB1 (rs687659), AL158151.3, PTPA, and IER5L (rs4387067). Those variants have epigenetic and genetic interactions with relevant genes with both cis and trans effects. In summary, we identified sex-shared associations at the single-variant level, sex-specific associations at the gene-based level, and genetic variants with significant differential effects between the sexes.