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, and nasal pharyngeal carcinoma (NPC), 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 lifecycle, 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. It is likely that innate immunity is particularly important in retroviral infections since it takes several days for the host to mount an immune response, too late to provide protection against proviral intergration into the genome. We are currently focusing our efforts on host genetic factors that confer innate immunity by blocking HIV-1 replication post-cell entry before productive infection is established.[unreadable] [unreadable] APOBEC3G, a cytodine deaminase 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 Vif (virion infectivity factor). After HIV-1Vif 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. APOBEG3G is a very strong candidate as a target for therapeutic intervention. The functional basis for these associations is not yet understood; however, we are now testing the hypothesis that these variant alleles are associated with altered gene expression.[unreadable] [unreadable] We are also investigating the evolution of APOBEC family members to determine if other APOBEC RNA editing enzymes are involved in HIV-1 diseases. Recent studies have found that APOBEC3F and APOBEC3B also strongly inhibit HIV-1 activity in vitro. We have genotyped haplotype tagging SNPs in AIDS cohorts and found they were weakly associated with more rapid progression to AIDS, primarily Pneumocytis carinii. In addition, we are investigating the role of RNA editing enzymes in AIDS-related lymphoma. HIV-1 associated non-Hodgkin lymphoma (NHL) is characterized by oncogenic changes in B cell DNA, induced by activation-induced cytidine deaminase AICDA. We have screened over 400 HIV-1-associated lymphoma cases and controls for 6 SNPs in the AICDA gene.[unreadable] [unreadable] 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.