Our 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 chronic infection and genetic variation leading to pathogenic outcomes including 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. Both targeted and genome-wide association studies (GWAS), have been used to discover variation associated with viral infections and their outcomes. These studies 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 to disparate incidence rates for infectious diseases and their outcomes (e.g. HIV-associated nephropathy or NPC) among diverse human populations. These studies provide insights into biological pathways that may lead to new therapeutics or genetic testing to improve clinical outcomes. Accomplishments 1) Association of HLA-DP with HBV clearance: Chronic HBV infection is extremely common in China, a region with the worlds highest prevalence rates for chronic hepatitis B and HBV-associated hepatocellular carcinoma (HCC). A recent GWAS performed in Asian populations on Asian samples securely identified a single nucleotide polymorphism (rs3077) in the HLA-DP region as associated with decreased risk of chronic HBV infection. It was not determined if the association with chronic hepatitis B was due to resistance to infection or increased rate of spontaneous viral clearance. We showed for the first time that the HLA-DB region was specifically associated with a 2.4-fold increase in spontaneous HBV clearance, but that it was not associated with increased risk of cirrhosis or HCC. Elucidation of the mechanism of HLA-DP interaction with HBV will be a critical step in our understanding of immune regulation of HBV infection, clearance, and vaccine response and may lead to targeted epidemic control strategies. It may also provide needed insights into the development of an effective vaccine to induce clearance in persons with chronic hepatitis B. The results of this study were published in Journal of Infectious Diseases. 2) Association of CCRL2 with AIDS and Pneumocystis pneumonia (PCP): PCP is a major AIDS defining condition and a common complication of immunosuppression. 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. Both non-synonymous and synonymous SNPs were genotyped in CCR5, CCR2, CCR3, CCRL2, CXCR6, CCR8 and CX3CR1 in HIV-1/AIDS natural history cohorts. We identified a non-conservative amino acid change in CCRL2 (Y167F) associated with more rapid progression to AIDS defining conditions, and specifically to the AIDS defining condition pneumocystis pneumonia (PCP). CCRL2 is involved in lung dendritic cell trafficking and may affect PCP by inducing inflammation. This is the first genetic association with an AIDS defining condition and brings renewed attention to the chemokine receptor nexus in HIV pathogenesis. Highlighting the role of inflammation may lead to better therapeutic options for persons presenting with PCP infection. 3) GWAS for HIV Infection and progression: GWA studies are an agnostic, unbiased method for detecting genetic factors associated with disease and traits with the overarching goals of revealing new pathways and targets for therapeutic intervention and for disease prediction. Our laboratory has participated in several GWAS for different HIV phenotypes including long-term non-progression, HIV infection susceptibility, and rate of progression to AIDS. GWAS studies scan hundreds of thousands of SNPS for association with a disease or trait;therefore, rigorous criteria for genome wide significance (by convention, p450). The results of this study have clinical relevance in genetic screening to identify persons at risk for developing NPC. 5) Association of APOL1 variants with HIV-associated nephropathy (HIVAN): HIVAN is a rapidly progressive disease affecting the kidney glomerulus. HIVAN is extremely common affecting approximately 10% of African Americans prior to effective antiretroviral therapies;HIVAN is rarely diagnosed in persons of non-African origin. Two APOL1 variant alleles, one comprising two codon-changing SNPs and the other a 6 base pair deletion removing two amino acids are found in 35% of African Americans;these variants are also extremely frequent in west African populations, presumably driven by survival advantage in APOL1 mutation carriers, which confers resistance to African sleeping sickness. Carriers of two APOL1 risk alleles (approximately 13-15% of African Americans) are at a much higher risk of several forms of non-diabetic kidney disease. In a highly collaborative study we showed that carriage of two APOL1 renal risk alleles increase the risk by 40-fold;the lifetime incidence for HIVAN among HIV-infected African Americans carrying two APOL1 variants is 50%. The attributable risk (AR) (68%) and explained fraction (EF) (37%) for APOL1 variants with HIVAN are quantitatively similar to the role of smoking in non-small-cell lung cancer risk (AR, 90% for males;EF, 12%). This study suggests that screening for APOL1 risk variants may have a role in personalized medicine for persons with African ancestry;it also explains a major global health disparity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010297-14
Application #
8348964
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2011
Total Cost
$445,875
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Winkler, Cheryl A; Nelson, George W (2017) A mouse recapitulating APOL1-associated kidney disease. Nat Med 23:411-412
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An, Ping; Penugonda, Sudhir; Thorball, Christian W et al. (2016) Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia. PLoS Genet 12:e1005921
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Yang, Xunjun; Guo, Xiuchan; Chen, Yao et al. (2016) Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma. Oncotarget 7:27838-47
Purswani, Murli U; Patel, Kunjal; Winkler, Cheryl A et al. (2016) Brief Report: APOL1 Renal Risk Variants Are Associated With Chronic Kidney Disease in Children and Youth With Perinatal HIV Infection. J Acquir Immune Defic Syndr 73:63-8
Rosenberg, Avi Z; Naicker, Saraladevi; Winkler, Cheryl A et al. (2015) HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment. Nat Rev Nephrol 11:150-60

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