Infectious diseases, in addition to causing acute and sometimes chronic infections, are also a leading cause of many common cancers including gastric cancer, cervical cancer, hepatocellular carcinoma, nasal pharyngeal carcinoma (NPC), Epstein Barr virus (EBV), and lymphoma. However, the role of host genetic factors in host resistance, chronic infection and pathogenesis leading to disease and/or malignancies is not well understood. Variation in genes encoding proteins providing acquired and innate immunity, proteins required for the completion of the viral life cycle, and tumor suppressors may affect individual susceptibility to the initial infection and the outcome of chronic infection. The investigation of host genetic factors that modify HIV-1 and Hepatitis C virus (HCV) infection and disease progression or that may predispose to NPC or heptocellular carcinoma may lead to better understanding of host resistance and pathogenesis in response to common pathogens and may lead to targeted therapeutic interventions. The cytodine deaminase, APOBEC3G, belonging to the APOBEC RNA-editing enzyme family, blocks HIV-1 replication by inducing G to A hypermutation in newly synthesized viral DNA; however, this suppression is blocked by HIV-1 virion infectivity factor (Vif). After HIV-1 Vif forms a complex with the host protein Cul5, it binds to APOBEC3G preventing the encapsulation of APOBEC3G in the newly formed virion. Wildtype HIV-1 is able to replicate in the presence of APOBEC3G whereas HIV-1 Vif strains cannot. We tested the hypothesis that genetic variants of the APOBEC3G gene may affect HIV-1 transmission and disease progression in 5 HIV-1 natural cohorts. Single nucleotide polymorphisms (SNPs) were screened in the 5'-untranslated region, 8 exons, exon-intron junctions, and 3'-untranslated region and seven SNPs were identified. The homozygous variant allele of H186R, a nonsynonymous change in exon 4 present only in African Americans, was associated with accelerated rate of progression to AIDS and death in African Americans. Two haplotypes carrying the variant allele of 199376G/C, located in intron 4, were also modestly associated with accelerated disease progression, separately in European- and African-Americans. The results suggest that APOBEC3G may play a role in the genetic modulation of HIV-1 disease. The functional basis for these associations is under investigation. APOBEG3C is a very strong candidate as a target for therapeutic intervention. We are now examining the evolution of APOBEC family members and determining if other family members such as APOBEC RNA editing enzyme are involved in HIV-1 diseases or associated neoplasms. We are now investigating the role of RNA editing enzymes in AIDS-related lymphoma. HIV-1 associated non-Hodgkin's lymphoma (NHL) is characterized by oncogenic changes in B cell DNA, induced by activation-induced cytidine deaminase (AICDA). The ability of HIV-1 Vif to suppress antiviral activity of APOBEC3G is specifically dependent on Cul5-SCF function, allowing Vif to interact with APOBEC3G and induce its ubiquitination and degradation. Thus, the Cul5-SCF pathway used by Vif may determine the differential viral activity conferred by APOBEC3G. We have genotyped 9 SNPs in Cul5 in the AIDS cohort. Four SNPs showed significant association with AIDS progression to CD4 200 and AIDS 93 in African Americans. These results suggest that Cul5 variant alleles may retard HIV-1 CD4 T cell depletion but do not block infection or prevent AIDS. Tripartite motif-containing 5 (TRIM5) is a protein that blocks HIV-1 infection of rhesus monkeys by binding to the capsid of the HIV-1 virion shortly after cell-entry. The viral genome is therefore not reverse-transcribed or integrated into the host genome. We have characterized the extent of genetic variation in the human TRIM5 gene and in a collaborative study investigated the genomic structure and phylogenetic relationships of primate TRIM5 genes. Interestingly, the gene is highly variant with an excess of codon-changing sites suggesting that this gene may be under selection for amino acid diversity. In addition, the extent of linkage equilibrium among intragenic SNPs and the haplotype structure of the gene both suggest that this gene may be under balancing selection and that a number of different TRIM5 genes provides selective advantage. We are now investigating the consequences of genetic variants on HIV-1 infection and progression to AIDS-defining conditions as well as on viral load and the trajectory of CD4 cell loss. These studies point to a role for innate immunity by TRIM5 against infection in human infectious disease. The use of haplotype tagging SNPs (htSNP) to identify hyplotype blocks in the human genome associated with disease is a key goal of the current hapmap project. However, the extensive disequilibrium within a haplotype block potentially confounds the concluding step of association analysis to identify specific polymorphism with a potential functional role in disease. The cluster of chemokine receptor genes surrounding CCR5 inChromosome 3p21 contains several known and potential functional genes affecting HIV-1/AIDS in a complex pattern of disequilibrium. A bootstrap-replicated multivariate survival analysis on six polymorphisms typed in five HIV-1/AIDS cohorts revealed a strong recessive association of a non-conservative amino acid change in CCRL2 (Y167F) with protection against AIDS, attributable to a specific protection against Pneumocystiscarinii pneumonia (PCP). Future plans are to investigate the role of CCRL2 in simian immunodeficiency virus (SIV)-infected macaques in a collaborative investigation. Significant progress has been made in the study investigating the role of EBV-associated NPC. We have recruited more than 400 NPC cases, their unaffected spouses who serve as a control, plus a parent or child for haplotype inference. A second case-control study to investigate the role of EBV persistence as determined by the presence of IgA antibody to viral capsid antigen (VCA) has also been established. The presence of this antibody is a significant risk factor for the development of NPC. We determined genotypes for 319 alleles in 34 microsatellite markers in the 18 Mb NPC-associated region. This regional fine mapping study suggests that the Chr 4 region may harbor genes associated with EBV persistence, a necessary prerequisite for NPV development.
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