Research By applying advances in molecular biology and genetics to population-based studies, epidemiologists are better able to understand the distribution and determinants of viral infections. Our research is focused on the role that human genetics plays in the natural history, transmission, and treatment of virus that are associated with cancer. We are also strongly interested in emerging viral infections. Role of Human Genetics Chemokine receptors act as HIV-1 coreceptors. A 32 base pair deletion mutation in the gene for the CC-chemokine receptor 5 (CCR5), a major HIV-1 coreceptor, has a 10% allele frequency in Caucasians. Individuals who are homozygous for the CCR5 mutation are resistant to HIV-1 infection, while HIV-1 infected heterozygotes have delayed progression to AIDS. Blockade of CCR5 has been proposed as therapy for HIV-1. Several large studies, totaling over 2,500 infected subjects, did not find any HIV-1 infected individuals who were homozygous for the CCR5 32 base pair deletion. However, we identified an HIV-1-infected hemophiliac who was homozygous for this allele, demonstrating that CCR5 is not required for infection. An intensive virological investigation revealed that the virus from this patient was restricted to the CXCR4 chemokine receptor, which acted as the HIV coreceptor. To determine whether CCR5 32 base pair deletion homozygotes have phenotypic expressions other than those related to HIV-1, we investigated this genotype among men not infected with HIV-1. We found that they were generally similar to CCR5 wild-type subjects, except for a higher prevalence of hypertension, higher lymphocyte counts, and higher hepatic enzyme levels in those infected with hepatitis C virus. Published data are inconsistent on the relationships between various genetic polymorphisms and AIDS risk. To better determine these relationships, we conducted an international meta-analysis of chemokine receptor polymorphisms and risk of AIDS. We found that both the CCR5-delta 32 allele and the CCR2-64I allele were associated with a better clincial course in HIV-1-infected patients. We found no evidence that homozygosity for the SDF-3'A allele altered the clinical course of HIV-1 infection. Both the natural history of HIV infection and the virus's response to anti-retroviral therapy are heterogeneous. It is known that some of the variation in natural history may be explained by polymorphisms in chemokine receptor genes. We showed that polymorphisms may also explain some of the heterogeneity in sustaining viral suppression, which has been observed among patients receiving potent anti-retroviral therapy. Studies are underway to examine genetic factors that alter susceptibility to hepatitis B virus, hepatitis C virus, and other infectious agents. These studies employ a variety of approaches including assays for genetic polymorphisms, gene expression and protein expression. HIV-1 RNA Levels We demonstrated that a single HIV-1 RNA level, measured early in the course of infection, strongly predicts long-term risk of AIDS. The level reflects the rate of viral replication, which is the driving force of AIDS pathogenesis. HIV-1 RNA levels are now routinely measured in the clinical care of HIV-1-infected patients. In a long-term cohort, we measured longitudinally HIV-1 RNA levels to determine whether HIV-1 remained in a steady state over time. For most subjects, HIV-1 RNA levels increased with time, with the rate of increase predicting the risk of AIDS. We also found that HIV-1 RNA values measured longitudinally were more predictive than the initial level alone. These findings were considered by a U.S. Public Health Service panel convened to make recommendations for optimal treatment of HIV-1-infected patients. More recently, we used the data from this research in a collaborative effort to demonstrate a mathematical relationship between HIV-1 RNA levels and survival time, such that a patient's cumulative exposure to viral replication predicts length of survival. Our measurements of HIV-1 RNA levels in subjects having a wide range of ages shed new light on HIV-1 pathogenesis. We found that HIV-1 RNA levels measured early in the course of infection were higher in subjects older than 35 years compared with younger subjects. This finding suggests that immune senescence, leading to higher HIV-1 replication rates, may explain the previously established association between older age and shorter AIDS incubation time. Human Herpesvirus 8 Human herpesvirus 8 (HHV-8) DNA sequences have been found in Kaposi's sarcoma tumor specimens and other malignancies, suggesting an oncogenic role for the virus. We determined that HHV-8 infection was frequent in homosexual men in the early 1980s, consistent with an epidemic of KSHV that paralleled the HIV-1 epidemic in the United States. We have also shown that HHV-8 is relatively common among injection drug users and that prevalence increases with longer duration of injection, which suggests that HHV-8 can be transmitted through blood.
| Bekker, Vincent; O'Brien, Thomas R; Chanock, Stephen (2009) Population genetics and comparative genetics of CLDN1, a gene involved in hepatitis C virus entry. Hum Hered 67:206-16 |
| Page-Shafer, Kimberly; Pappalardo, Brandee L; Tobler, Leslie H et al. (2008) Testing strategy to identify cases of acute hepatitis C virus (HCV) infection and to project HCV incidence rates. J Clin Microbiol 46:499-506 |
| Ioannidis, John P A; Boffetta, Paolo; Little, Julian et al. (2008) Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 37:120-32 |
| O'Brien, Thomas R; Kachapati, Kritika; Zhang, Mingdong et al. (2007) HCV infection clearance with functional or non-functional caspase-12. Scand J Gastroenterol 42:416-7 |
| Kachapati, Kritika; O'Brien, Thomas R; Bergeron, Julie et al. (2006) Population distribution of the functional caspase-12 allele. Hum Mutat 27:975 |
| Blattner, William A; Oursler, Kris Ann; Cleghorn, Farley et al. (2004) Rapid clearance of virus after acute HIV-1 infection: correlates of risk of AIDS. J Infect Dis 189:1793-801 |
| Tanaka, Yasuhito; Pfeiffer, Ruth; Yeo, Anthony E T et al. (2004) PCR-probe capture hybridization assay and statistical model for SEN virus prevalence estimation. J Med Virol 73:123-30 |
| Maloney, E M; Hisada, M; Palmer, P et al. (2000) Human T cell lymphotropic virus type I-associated infective dermatitis in Jamaica: a case report of clinical and biologic correlates. Pediatr Infect Dis J 19:560-5 |
| Hayes, R B; Pottern, L M; Strickler, H et al. (2000) Sexual behaviour, STDs and risks for prostate cancer. Br J Cancer 82:718-25 |
| Hisada, M; Rabkin, C S; Strickler, H D et al. (2000) Human papillomavirus antibody and risk of prostate cancer. JAMA 283:340-1 |
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