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 targeted gene, genome wide association study (GWAS), and functional approaches to discover genes associated with HIV-1, HBV infection and HBV-associated liver cancer. We have also formed international collaborations with researchers in South Africa and China to mentor fellows, build capacity, and perform research that address important public health questions (i.e. HIV in South Africa and HBV-associated liver cancer in China). 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 resulting in HIV resistance 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 were published in PLos Genetics. 2) As we previously reported, APOL1 variants are associated with HIV-associated nephropathy African Americans (OR 27) and South Africans (OR 89). In a collaborative study with the Pediatric HIVAIDS Cohort Study (PHIV), we found, using a nested case control study of 451 participants, that there was a 3.5-fold increased odds of chronic kidney disease in children carrying 2 copies of APOL1 risk alleles, which the Journal of Acquired Immune Deficiency Syndrome. This study carries important implications for sub-Saharan Africa where pediatric HIV infection is very common and 3-25% carry two APOL1 risk alleles. 3) In a collaborative study with researchers at University of KwaZulu-Natal in South Africa, we showed that a variant in the regulatory region of the cyclophilin gene, PPIA, which aids in HIV capsid uncoating after HIV cell entry, upregulates cyclophilin expression after HIV infection. Individuals carrying this variant have enhanced viral replication. These data support on-going efforts to develop drugs that target host proteins rather than HIV, since HIV may develop resistance or escape mutations to therapies targeting HIV proteins. This study was published in the Journal of Acquired Deficiency Syndrome. 4) We reported in the journal Oncotarget the results of a study to investigate the role of telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular (liver) carcinoma (HCC). HCC is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths, due to combination of environmental exposures (e.g., aflatoxin) and the high prevalence of chronic HBV infection. Telomerase reverse transcriptase (TERT) promoter mutations are among the most frequent noncoding somatic mutations in multiple cancers, including hepatocellular carcinoma (HCC). The clinical and pathological implications of TERT promoter mutations in hepatitis B virus (HBV)-associated HCC have not been resolved. We sequenced the TERT promoter region for hotspot mutations in HCC tissues and performed immunostaining for TERT protein expression from HBV-associated HCC in Chinese patients. Of 276 HCC tumor DNA samples sequenced, 85 (31%) carried TERT promoter mutations. We found that TERT promoter mutations were more frequent in those with low alpha-fetoprotein (AFP) serum levels, a marker for liver cancer (p = 0.03), advanced age (p = 0.04), and in those lacking HCC family history (p = 0.02). TERT protein levels did not differ between mutated and non-mutated tumor tissues; but they were higher in HCC compared to normal liver tissues (p =0.001). We found that similarly to several other cancers, TERT promoter mutations were frequently observed somatic mutations in HCC of Han Chinese with HBV infection. Detection of TERT promoter mutations in those with low levels of AFP may aid diagnosis of HCC with atypical presentation.
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