ZIA BC 010297 (ZIA) | |||
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Title | Identification of Genetic Factors Associated with Infectious Diseases | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Winkler, Cheryl | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $306,856 | Project Dates | 01/01/1997 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (1.0%) Cancer (100.0%) Digestive Diseases (15.0%) Genetic Testing (25.0%) Herpes - Other (35.0%) |
Cervical Cancer (5.0%) Kaposi Sarcoma (30.0%) Kidney Cancer (1.0%) Kidney Disease (20.0%) Liver Cancer (15.0%) Sarcoma (30.0%) Urinary System (20.0%) Wilm's Tumor (1.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
This project's focus is on two infectious diseases that continue to have tremendous impact on global health. Human Immunodeficiency Virus (HIV) is pandemic and Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma (HCC) is prevalent in East Asia, globally affecting millions of people and having no cure. The objective of this project is to identify host factors that contribute to the occurrence and development of these, and potentially other, infectious diseases. We aim to identify host genetic factors that affect host innate restriction or susceptibility in acquisition, replication, and pathogenesis of viral pathogens, and carcinogenesis, the mechanisms of which are not fully understood. The identification of host proteins involved in viral replication, in innate or acquired immunity, or in carcinogenesis pathways will provide critical insights for the rational development of antiviral drugs and effective vaccines. Our strategy is to search for genetic variants that differentially affect rates of infection, or the course of pathogenesis, and which thereby identify the variant-containing gene as conferring restriction or susceptibility to infection or progression. We are using both targeted gene and genome wide association study (GWAS) approaches, including Illumina and Affymetrix chip technologies, to discover genes associated with HIV-1, HBV infection and HBV-associated liver cancer. Accomplishments 1) Human APOBEC3 cytidine deaminases are a family of intrinsic retroviral resistance factors that edit viral RNA, leading to nascent DNA hypermutation. However, HIV-1 viral infectivity factor (Vif) binds to APOBEC3 proteins and targets it for degradation via the ubiquitination-proteosomal pathway; therefore HIV is resistant to APOBEC3 restriction. APOBEC3F (A3F) anti-HIV-1 activity is partially resistant to Vif degradation unlike APOBEC3G. In vitro studies have shown that A3F edits the HIV-1 genome similarly to APOBEC3G, albeit with different target sequences and with weaker anti-HIV activity. To assess the in vivo effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-SNP haplotype of A3F tagged by a codon-changing SNP (p. I231V) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (RH = 0.71, 95% CI: 0.56, 0.91). The slower rate of progression to AIDS was mainly afforded by delayed development of pneumocystis pneumonia (PCP) (RH= 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. The HIV-1 Vif protein, which shares sequence homology and structurally mimics the A3F region containing p.I231V, may have evolved to adapt to the host p. I231V isoforms, suggesting that the A3F I231V change may modify A3F-vif interaction. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. The results have been formalized for publication and submitted. 2) ZNRD1 was identified as a host protein required for the completion of the HIV lifecycle in a genome-wide screen using small interfering RNA gene silencing. Subsequently, a genome-wide association study (GWAS) of host determinants for HIV-1 disease identified an association of single nucleotide polymorphisms (SNPs) in the ZNRD1 region with CD4 T-cell depletion. To address the effects of SNPs in the ZNRD1 region on human immunodeficiency virus type 1 (HIV-1) infection and progression to clinical outcomes, we determined the association of ZNDR1 variants in 5 US-based HIV-1 longitudinal cohorts (n = 1865). SNP function was evaluated by electrophoretic mobility shift assay and promoter luciferase assay. A haplotype in the ZNRD1 gene showed significant association with a 35% decreased risk of HIV-1 acquisition (OR = 0.65, 95% CI, .4 |