The major objectives of my laboratory group are to identify host factors that contribute to infectious and other complex diseases with the goals of identifying targets for therapeutic intervention, improving diagnosis, and informing interpretation of clinical and vaccine trials. Viral infections are now recognized as major causes of common cancers, but little is understood about the interplay between infection and host genetic factors leading to cancer development in persons infected with HIV or the hepatitis C and B viruses. Both HCV and HIV have no preventive vaccines and no curative treatment and are highly prevalent in the global population. Our focus has been to discover genetic factors modulating HIV-1, HCV, and HBV infections and associated diseases. To this end, we have developed international collaborations to establish case-control and cohort studies in China and southern Africa, in addition to five established U.S.-based HIV-1 longitudinal cohorts, to investigate HIV-1, HBV, and HCV as well as the common carcinomas, NPC and HCC, associated with the EBV and HB viruses, respectively. We have established a collaboration with the Botswana Harvard Partnership to investigate the genetic correlates of HIV-1 infection, progression, and response to antiretroviral therapy in a region severely impacted by HIV-1 subtype C infection, the subtype responsible for the majority of HIV-1 infections globally. Using both targeted gene and genome wide association approaches, we have employed high throughput genotyping technologies to discover genes associated with HIV-1-associated nephropathy and with progression to AIDS. Whenever a significant association is observed, the laboratory uses fine mapping to identify putative causal alleles and functional assays to assess effects on gene transcription and protein levels. <B>Accomplishments</B>APOBEC3G is a human innate resistance factor to HIV-1 that is incorporated into budding virions. APOBEC3G, in the absence of HIV-1 encoded viral infectivity factor (vif), causes hypermutation of the nascent cDNA, effectively preventing viral infection. Human APOBEC3Gs anti-HIV-1 activity is disarmed by HIV-1 vif by interaction with Cullin5 (CUL5) complex leading to the degradation of APOBEC3G. Through a study of HIV-1 natural history cohorts with different clinical outcomes, we have previously shown that polymorphism APOBEC3G gene is associated with rate of progression to AIDS and trajectory of CD4+ T cell decline in HIV-1-infected persons. We also discovered that polymorphism in CUL5 influences the rate of CD4+ T-cell depletion. Seven <i>APOBEC3</i>genes (A-H) cluster together on a single chromosome and most confer anti-HIV-1 activity. We investigated the influence of genetic variation in all <i>APOBEC3</i>genes on HIV-1 infection and disease progression. APOBEC3B has been shown to inhibit HIV-1 replication in vitro and is the only APOBEC3B protein not inhibited by HIV-1 vif. More than 22% of the global population carry a deletion of the APOBEC3B gene resulting in abrogation of APOBEC protein. We examined the impact of the <i>APOBEC3B</i>gene deletion on HIV-1 infection and disease progression in more than 4000 subjects. We found that individuals who do not express APOBEC3B protein because they carry two copies of the gene deletion were much more likely to be infected with HIV-1 (OR = 7.37, P=0.024). Homozygosity for the deletion was also associated with more rapid progression to AIDS (RH = 3.82, P=0.03) and higher viral load (p=0.048). The <i>APOBEC3B</i>deletion may have considerable impact on the HIV-1 epidemic in populations with Asian ancestry where the <i>APOBEC3B</i>deletion allele is much more common. We also found that codon changing mutations in <i>APOBEC3F</i>resulted in a gain of function of antiretroviral activity. APOBEC3F strongly inhibits HIV-1 and is partially resistant to vif. We found that two amino acid changing variants were associated with delayed progression to AIDS (RH=0.70, P= 0.007). The relative contribution of each APOBEC3 gene and their interaction on viral infection are under investigation. Recently, it was reported that the Duffy antigen receptor for chemokine (DARC) null phenotype increased risk of HIV-1 infection in African Americans by 40%. It was suggested that 11% of the increased burden for HIV infection in Africa was due to the absence of the DARC protein on the surfaces of red blood cells. The DARC null phenotype occurs in more than 90% of subSaharan Africans, and conveys resistance to <i>Plasmodium vivax</i>malaria. We examined the same polymorphism in a group of African Americans, more than 90% of whom were infected by injecting drug use and found no association between DARC null group and the DARC positive group for infection susceptibility. Together with other studies, we effectively ruled out DARC as a genetic cause for the increased burden of HIV infection in sub-Saharan Africa. A recent genome-wide association study (GWAS) of host determinants for HIV-1 disease revealed that SNPs near or in genes <i>HLA-C</i>, <i>ZNRD1</i>and <i>ZNF39</i>were associated viral load setpoint or disease progression among European HIV-1 cohorts. We investigated the effect of the SNPs in the <i>ZNRD1<I/I>region on HIV-1 infection and progression in five U.S-based HIV-1 longitudinal cohorts. After adjusting other known covariates including <i>HLA</i>alleles, <i>HLA-C</i>was strongly associated with favorable outcomes for AIDS and death (Relative hazard [RH] = 0.72, P = 0.0003) and (RH=0.64, P=6.3 x 10-6) in European Americans. A haplotype in the <i>ZNRD1</i>gene showed significant association with protection of HIV-1 infection, which was independent of HLA-C, thus providing a novel evidence for an independent role of <i>ZNRD1</i>. Previously <i>ZNDR1</i>was shown to be an HIV dependency gene in an in vitro experiment using silencing RNA to knock-down host genes. The findings suggest independent and significant roles of <i>HLA-C</i>and <i>ZRND1</i>in modulating HIV/AIDS. Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus (HCV) clearance: The immune response is critical in determining the outcome of HCV infection. Interleukin (IL)-18 is a pivotal mediator of Th1/Th2 driven immune response. Two <i>IL-18</i>promoter polymorphisms known to affect IL-18 expression levels were examined for their role in HCV clearance or persistence. Genotyping was performed among African American injecting drug users (IDUs) with HCV clearance and HCV persistence, and among European American hemophiliacs mainly infected through plasma transfusion. <i>IL-18</i>polymorphisms were significantly associated with HCV clearance in intravenous drug users. Among IDUs, IL18 -607A (Odds ratio [OR], 3.68;95% confidence interval [CI],1.85-7.34) and IL18 -137C (OR, 2.33;95% CI, 1.24-4.36) were significantly associated with HCV clearance. These results suggest that <i>IL18</i>promoter polymorphism may affect the outcome of HCV infection in certain risk groups. This work suggests that therapies using immune modification may promote HCV clearance in persons with chronic infections.
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