The objectives are to identify genetic factors contributing to infectious diseases with the goals of identifying targets for drug development and improving diagnosis/prognosis. Infections are major causes of cancers: HIV, EBV, or the hepatitis C virus (HCV) and hepatitis B virus (HBV) contribute to AIDS-associated malignancies, nasopharyngeal carcinoma (NPC) and hepatocelluar carcinoma (HCC), respectively. Little is understood about the interplay between infection and genetic variation leading to cancer in persons infected with these viruses. Both HCV and HIV have no preventive vaccines or no curative treatment and are highly prevalent in the global population. We focused on genetic factors associated with susceptibility/resistance to HIV-1, HCV, and HBV infections and disease outcomes. International collaborations for case-control and cohort studies in China and Africa, in addition to five U.S.-based HIV-1 longitudinal cohorts, have been developed to investigate HIV-1, HBV, and HCV as well as NPC and HCC, respectively. Using both targeted and genome wide association studies (GWAS), state-of-the art technologies have been used to discover variation associated with these infections and their outcomes. These studies should explain in part the variance observed among individuals in viral infection, progression, and disease outcomes. In addition, we will gain insights of the contribution of genetic variation among diverse human populations to disparate prevalence rates for infectious diseases and their outcomes (e.g. HIV-associated nephropathy or NPC). These studies will provide insights into biological pathways that may lead to new therapeutics or genetic testing to improve clinical outcomes. Accomplishments Identification of renal susceptibility mutations in APOL1: In 2008 we identified a region on Chr 22 associated with increased risk of HIV-associated nephropathy as well as other severe forms of kidney disease. The renal risk alleles were frequent in African Americans but rare in Europeans thereby providing a genetic basis for a major health disparity. We reported that the region harboring MYH9 was under recent selection in west Africans but not in other African populations suggesting that the renal risk alleles may be tracking mutations that provide protection against a pathogen. In a collaborative study we reported that two variants in APOL1 confer protection against sleeping sickness-causing Trypanosoma brucei rhodesiense (T.b.r). Plasma from individuals carrying any combination of the two mutations lyse T.b. r., conferring protection against T.b.r. sleeping sickness. Analogous to the sickle cell trait, APOL1 mutations provide protection against a lethal pathogen in carriers but homozygotes and complex heterozygotes for the risk variants are more vulnerable to HIV-associated nephropathy. Development of an African cohort for a GWAS: In a collaboration with Harvard and the Botswana-Harvard Partnership, over 6,000 DNA samples have been collected from individuals with HIV-1 type C. Botswana has one of the highest HIV prevalence rates in the world. The study is powered to investigate the influence of genetic factors on HIV acquisition, antiviral treatment efficacy and adverse events, and viral load/CD4 trajectories. These samples will be used for a GWAS and next generation sequencing to identify common and rare variants that associated with HIV-1 pathogenesis in southern Africans. APOBEC3 Genes and their role in HIV/AIDS: The APOBEC3 gene family confers resistance to retroviruses by deaminating cytodine leading to pervasive hypermutation of HIV. We tested the association of genetic variants in all APOBEC3 genes with HIV/AIDS. APOBEC3F inhibits HIV-1 and unlike APOBEC3G is partially resistant to HIV-mediated degradation. Two codon-changing variants in APOBEC3F were associated with delayed time to AIDS. A 29.5-kb deletion removes the entire APOBEC3B gene. The homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition, progression to AIDS, and viral set point. These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1 acquisition and progression to AIDS. We tested for association of APOBEC3G mRNA levels and genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4 T-cell counts as outcomes in South African women at high risk for HIV-1 subtype C infection. APOBEC3G expression levels were higher in HIV-negative compared to HIV-positive women, including matched pre- and post-infection samples from the same individuals. Two variants were associated with high viral loads and low CD4 T-cell levels, respectively. These data suggest that APOBEC3G transcription is rapidly downregulated upon HIV-1 infection and APOBEC3G variation may affect early HIV-1 pathogenesis. Chr 3 chemokine receptor gene family: Chr 3p21-22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. We resequenced 7 chemokine receptors in 144 individuals representing extreme phenotypes for HIV progression and infection;six codon-changing SNPs were discovered. SNPs were genotyped in CCR5, CCR2, CCR3, CCRL2, CXCR6, CCR8 and CX3CR1 in HIV-1/AIDS natural history cohorts. Significant independent associations with AIDS progression were identified for CCR3 and CCR8 . Notably, we identified a non-conservative amino acid change in CCRL2 (Y167F) association with pneumocystis pneumonia (PCP). CCRL2 is involved in lung dendritic cell trafficking and may affect PCP by inducing inflammation. HLA association with NPC: A case-control study of NPC cohort from Guangxi, a region with one of the highest NPC incidences in the world revealed strong associations with the HLA region. This study showed for the first time that A*0206, a unique A2 subtype to South and Southeast Asia, is associated with a high risk for NPC. Factors associated with risk were more frequent in this population. These results suggest that the high rate of NPC in the Guangxi population is due in part to the higher frequencies of NPC-HLA risk alleles. GWAS for HIV/AIDS: We have contributed to three international GWASs to discover genetic factors associated with unusually fast or slow progression to AIDS. The USA-based GWAS identified a SNP near the PROX1 gene strongly associated with delayed progression to AIDS. We replicated this association in a larger natural history HIV cohort study. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. The second GWAS also compared rapid to slow progressors to AIDS in a French cohort. This study identified a SNP in the CXCR6 gene that was associated with extremely low viral load in elite controllers and was replicated in three cohorts. The third GWAS was performed on 5 USA cohorts. This study identified PARD3B as a novel protective gene. These studies adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis. GWAS for HBV: We tested the effects of HLA-DP SNPs on major HBV outcomes in a Chinese HBV cohort (n=1700) comprising HBV resistance, clearance, chronic infection, cirrhosis and HCC. SNP rs3077 is found to be a major predictor for HBV clearance (P = 4.7x10-10), but has no influence on more cirrohsis or heptocellular carcinoma in persons with chronic infection. This replicates and confirms a published GWAS performed in Asians.
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