Biography

Dr. O'Brien received undergraduate and medical degrees from the University of Michigan, and an M.P.H. from the Harvard School of Public Health. He was an Epidemic Intelligence Service Officer and Medical Epidemiologist with the Centers for Disease Control and Prevention from 1985 to 1992, when he joined the NCI Viral Epidemiology Branch. Dr. O'Brien's primary research interests involve studies on the transmission and natural history of oncogenic viruses, especially the human immunodeficiency viruses (HIV) and hepatitis C virus. He is the author of more than 85 scientific publications.

Research Interests

Oncogenic Viruses and Human Genetics

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 focusing on HIV-1 RNA levels as markers of pathogenesis and prognosis, as well as on the role of genetic polymorphisms of chemokine receptors genes in HIV-1 natural history, transmission, and treatment.

Chemokine Receptor Gene Polymorphisms

Chemokine receptors play an essential role in immune cell trafficking, but also 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 are conducting an international meta-analysis of chemokine receptor polymorphisms and risk of AIDS.

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 recently 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.

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.

Kaposi's Sarcoma-Associated Herpesvirus Studies

Kaposi's sarcoma-associated herpesvirus (KSHV) DNA sequences have been found in Kaposi's sarcoma tumor specimens and other malignancies, suggesting an oncogenic role for the virus. In an interdisciplinary collaborative effort, we developed serologic and polymerase chain reaction assays for KSHV infection. Applying these assays, we determined that KSHV infection was relatively frequent in homosexual men in the early 1980s, consistent with an epidemic of KSHV that paralleled the HIV-1 epidemic in the United States.

Keywords

• acquired immunodeficiency syndrome (AIDS), chemokine receptors, genetics, hepatitis B virus, hepatitis C virus, HIV-1 RNA levels, human immunodeficiency viruses (HIV), Kaposi's sarcoma-associated herpesvirus (KSHV), incubation period, Kaposi's sarcoma, viral transmission, virology

Selected Publications

• Michael NL, et al. "Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32." J Virol 1998; 72:6040-6047.
• O'Brien TR, et al. "Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma." J Infect Dis 1999; 80:1010-1017.
• O'Brien TR, et al. "Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy." AIDS 2000; 4:821-826.
• Ioannidis JP, et al. "Effects of CCR5-D32, CCR2-64I and SDF-1 31A alleles on HIV-I disease progression: An international meta-analysis of individual patient data." Ann Int Med 2001; 135:782-795.

Collaborators

DCEG Collaborators

• Robert Biggar, M.D.; Eric Engels, M.D., M.P.H.; James Goedert, M.D.; Michie Hisada, M.D., Sc.D.; Philip Rosenberg, Ph.D.; Denise Whitby, Ph.D.

Othe NCI Collaborators

• Mary Carrington, Ph.D.; Michael Dean, Ph.D.; Stephen O'Brien, Ph.D.

Other NIH Collaborators

• Philip Murphy, M.D., National Institute of Allergy and Infectious Diseases
• Barbara Rehermann, M.D., National Institute of Diabetes and Digestive and Kidney Diseases

Other ScientificCollaborators

• Louis Aledort, M.D., Mount Sinai Medical Center, New York, NY
• Alan Cohen, M.D., Children's Hospital of Philadelphia, Philadelphia, PA
• M. Elaine Eyster, M.D., Pennsylvania State University Hershey Medical Center, Hershey, PA
• Angelo Hatzakis, M.D., Athens University Medical School, Athens, Greece
• John Ioannidis, M.D., University of Ioannina School of Medicine, Ioannina, Greece
• Craig M. Kessler, M.D., Georgetown Medical Center, Washington, D.C.
• Naomi Luban, M.D., Children's National Medical Center, Washington, D.C.
• Cindy Lessinger, M.D., Tulane University, New Orleans, LA
• Michael Lederman, M.D., Case Western Reserve University, Cleveland, OH