Training

STD/AIDS Research Training Fellowship Program

Viral STD Research Track

Denise A. Galloway, Ph.D.; Larry Corey, MD - Co-Directors

Overview: The Viral STD Track offers laboratory-based or clinical research on various viral STDs, to develop investigators able to pursue independent research careers, working in viral pathogenesis, viral immunology, clinical virology or diagnostic virology. The faculty members in this track study human and animal retroviruses: HIV-1, HIV-2, HTLV-1, HFV, SIV, FIV, FeLV; herpesviruses HSV-1 and 2, CMV, EBV, HHV-6 and HHV-8 (KSHV); human papillomaviruses (HPVs); and hepatitis C virus (HCV).

Predoctoral students are PhD candidates in the UW Departments of Microbiology and Pathology, or in the Interdisciplinary Programs in Pathobiology (now affiliated with Department of Global Health) and Molecular & Cellular Biology. Students may apply for this track once they have completed most of their course work in relevant disciplines(or 2 years of medical school for our MD/PhD students), their three lab rotations, and have selected a thesis project in the laboratory of one of the faculty in this track. A thesis committee is selected, often containing several Viral STD track faculty, who monitor the student’s progress twice yearly, suggest appropriate additional course work, and administer qualifying exams. First-author publications in peer-reviewed journals are expected. Students generally obtain their PhD within 5 years of dissertation research.

PhD Fellows apply to individual Viral STD Track faculty members for postdoctoral positions, and like the predoctoral trainees, attend the summer course on Principles of STD research, as well as research meetings relevant to their research (see below); audit didactic classes as needed; become skilled at research; and hone their skills in writing publications and grants, and in oral presentation. MD fellows have completed a residency and enter one of the Clinical Fellowship programs at UW, particularly Infectious Diseases, but also in other specialties (e.g. Pediatrics/Adolescent Medicine, OB/GYN). They participate in the same courses and meetings as the PhD fellows, and more often attend additional didactic courses to update their basic science knowledge. For those with minimal research experience the training period in the laboratory is often longer (~5 years), and will include both training grant support and other awards such as K08s from the NIH or HHMI physician scientist grants. Learning to write these grant applications is a key part of training for fellows. The MD fellows also develop clinical skills in management of STDs and HIV infection, described above.

Didactic Curriculum and Additional Seminar Training Opportunities: All trainees participate in the STD/AIDS Core Curriculum. In addition all pre-docs take the Graduate Virology class, Human Pathogenic Viruses (MCB532), organized by Drs. Linial, Galloway and Emerman. Many postdocs audit this class. Additional classes of interest taught by our senior training faculty include Evolution and Genetics; Molecular Basis of Neoplasia; Graduate Virology, Graduate Immunology and others. Research Group meetings, in which both pre- and postdoctoral trainees in this track participate, include Retroviruses (weekly), Medical Virology (weekly), Cancer Biology (weekly), FHCRC Basic Science/Human Biology (weekly), CFAR Pathogenesis Research (monthly); Papillomaviruses (monthly), and FHCRC Virology Division (weekly, plus semiannual retreat days). Trainees attend the appropriate meetings regularly and present their research annually at one of these meetings.

Faculty: 2 training faculty and 15 resource faculty participate in this track.

• Research Training Opportunities: Abbreviated descriptions of research activities of the training faculty are provided below:
  
  
• Corey, Lawrence MD Track Co-Director, Training Faculty The research areas associated with Dr. Corey include studies of the immunobiology of HSV infection, HSV-2 and HIV vaccine development, and infections in the bone marrow transplant patient. The Herpes Group program involves studies in HSV, CMV, HHV-6, and HHV-8. The clinical program in genital herpes includes a wide variety of studies looking at the natural history of subclinical shedding, transmission of HSV to sexual partners and infants, and evaluation of the interrelationship between the host response and viral reactivation of infection. Studies defining the transmission of HHV-8 infection among a variety of cohorts in both the United States and internationally are also ongoing. Dr. Corey is the PI of the NIAID supported HIV Vaccine Trials Network (HVTN), a multicenter, international program for developing and testing candidate HIV vaccines.
  
  
• Galloway, Denise, PhD Track Co-Director, Training Faculty The goal of the Galloway laboratory is to understand the mechanism by which human papillomaviruses (HPVs) contribute to neoplasia. Much of the work focuses on the mechanisms by which the oncoproteins E6 and E7 immortalize human epithelial cells, the natural history and protective function of antibodies during HPV infection (with Dr. Koutsky), and the identification of epitopes of protective antibodies.
  
  
• Beretta, Laura, PhD Training Faculty Dr. Beretta's research focus is the characterization of the hepatitis virus-host interactions and identification of markers for early detection of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) and hepatitis C virus (HCV). The Beretta Lab uses the new self-replicating HCV cell culture system to measure viral replication directly. Following from their work on viral replication in host cells, they continue searching for markers useful for early detection of liver disease and for markers of disease progression in patients singly infected or co-infected with HIV. Candidate markers have been selected following the analysis of a cohort of patients with HBV-associated liver cirrhosis or HCC, enrolled in The Gambia Hepatitis Intervention Study sponsored by the World Health Organisation (WHO); (b) a cohort of patients with HBV-associated liver cirrhosis or HCC, enrolled in the WHO’s Liver Cancer Study of the National Cancer Institute of Thailand; and (c) cohorts of patients with HCV-associated liver cirrhosis or HCC, enrolled in the U.S.
  
  
• Collier, Ann, MD Training Faculty Ongoing clinical research projects include studies of antiretroviral treatments for HIV including long term outcomes, the natural and treated history of primary HIV infection, the effects of antiretrovirals on neurological aspects of HIV infection, and pharmacokinetic studies. Multiple antiretroviral therapies are under investigation. Ongoing treatment trials include Phase I, II, III, and IV studies, and are both single and multicenter in nature. Ongoing collaborators include Drs. Coombs, Mullins, McElrath, Marra, Holte, Kitahata, and Frenkel.
  
  
• Coombs, Robert, MD, PhD Training Faculty We focus on the pathogenesis of HIV-1 and the quantification of viral load in the setting of therapeutic clinical trials involving both adult (Dr. Collier, ACTG Network) and pediatric (Dr. Frenkel, IMPAACT Network) HIV-1 infected subjects. With Dr. John Krieger (Department of Urology) and others at the UW, a research program is ongoing to elucidate shedding of HIV-1 in the male and female genital tracts and regulation of HIV-1 shedding by local inflammation (Drs. Hitti and Michael Boeckh).
  
  
• Emerman, Michael, PhD Training Faculty This laboratory studies the regulatory and structural genes of HIV to understand the molecular basis for pathogenicity, including tropism of HIV in dividing and non-dividing cells, characterization of the early stages of the viral lifecycle, and host cell defenses against HIV and other retroviruses.
  
  
• Frenkel, Lisa, MD Training Faculty Dr. Frenkel’s research focuses on practical questions related to the prevention of HIV-1 infection in infants and the prevention, detection and treatment of antiretroviral (ARV)-resistant virus in children and adults. Current projects focus on the dynamics of ARV-resistant HIV-1 mutants, the selection, transmission, and the detection of ARV-resistant HIV-1 in women and infants as a result of peripartum chemoprophylaxis, the development of rapid assays for HIV-1 diagnosis in early infancy, and the detection of clinically relevant ARV-resistant mutants in resource-limited communities; Projects include collaborative studies with colleagues in India, Mozambique, Peru, Thailand, USA, and Zimbabwe.
  
  
• Gottlieb, Geoffrey MD, PhD Junior Training Faculty Dr. Gottlieb focuses on the effect of antiretroviral therapy (ART) on HIV-2 disease outcomes, emergence of drug resistance, and genital HIV shedding in Senegal, West Africa; the differences between the natural history, clinical, immunologic and virologic aspects of HIV-1 and HIV-2 infection; and the effects of dual infection with HIV-1 and HIV-2 on disease outcomes. This work is an ongoing collaborative effort between the UW and the University of Dakar, Senegal, since the early 1990’s. The “Superinfection Project” is a collaborative effort between Jim Mullins’ group at the UW and the MACS cohort, to elucidate the virologic and host factors associated with dual infection.
  
  
• Gretch, David, MD, PhD Training Faculty Research in Dr. Gretch’s laboratory addresses several aspects of chronic hepatitis C in humans. Studies include systematic longitudinal investigation of viral replication, immune responses, quasispecies formation and disease progress in an Alaskan Native American (ANA) cohort (1000 patients), the HALT-C Trial (800 patients with advanced hepatitis; and over 100 HCV-infected subjects with and without coinfection with human immunodeficiency virus (HIV). A primary fetal hepatocyte cell culture model is under development, as are models of HCV hematotropism.
  
  
• Hu, Shiu-Lok, PhD Training Faculty The primary interests of Dr. Hu's laboratory are HIV pathogenesis and approaches for the prevention and treatment of AIDS. Currently, the staff pursues three major research areas: design and evaluation of vaccines against HIV and related primate lentiviruses; structural, functional, and immunogenic studies of HIV-1 envelope proteins; and pathogenesis of HIV-2.
  
  
• Katze, Michael, PhD Training Faculty The Katze lab is focused on understanding the complex interplay between a broad range of viruses (influenza, SARS-associated coronavirus, HSV,HIV, SIV), the cells they infect, and the mechanisms used by viruses to avoid the innate antiviral response. Technologies include DNA microarrays and mass spectrometry to study changes in cellular gene expression and protein production that occur in response to virus infection. Katze also has a National Institute on Drug Abuse P30 Center focused on using genomic and proteomic technologies to better understand molecular mechanisms underlying hepatitis C virus associated liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma.
  
  
• Kiviat, Nancy MD Training Faculty Dr. Kiviat’s HPV Research Group, in collaboration with Dr. Koutsky, has been involved in studies regarding the natural history of incident HPV infection in young women, the effect of HIV infection on development of anal neoplasia in men and cervical neoplasia in women, the association of HPV with skin cancers, and the first evaluations of HPV vaccines. The HPV Research Group has participated in carries out much of its research collaboration with the University of Dakar in Senegal, West Africa. Current HPV includes, epidemiology of anal HIV-1 infection, epidemiology & biology of HIV and cervical neoplasia, and the epidemiology of HPV and skin cancer.
  
  
• Koelle, David, MD Training Faculty The laboratory focuses on the human cellular immune response to herpes simplex virus (HSV) and orthopoxviruses (vaccinia, smallpox). Major questions include the search for an effective HSV vaccine, an explanation for the great spectrum of disease severity seen in the human population, and the mechanisms by which HSV-specific T cells migrate from the blood into infected tissues. We have a grant to sequence wild-type HSV-2 isolates to determine if T cell immune escape mutations occur, as have been documented for HIV and HCV. This project, with Dr. Wald, examines the relationship between HLA type and HSV-2 severity.
  
  
• Lagunoff, Michael, PhD Training Faculty Kaposi’s Sarcoma (KS) is the most common tumor of AIDS patients world-wide and is often the cause of death. Our lab is primarily interested in how latent KSHV infection alters endothelial cells. We have found that KSHV alters the differentiation state of endothelial cells causing blood endothelium to differentiate to lymphatic endothelial cells. In addition, we study signal transduction pathways involved in angiogenesis and growth of endothelial cells activated by latent KSHV infection.
  
  
• Lingappa, Jaisri, MD, PhD Training Faculty The primary focus of the Lingappa lab is understanding viral host interactions involved in assembly of HIV and HCV. We are studying the subcellular localization of viral and cellular protein assembly intermediates, defining other cellular proteins present in these intermediates, and determining how these intermediates are targeted to membranes during assembly. A cell-free capsid assembly system has now been successfully used as a screen to identify anti-viral compounds that inhibit production of all flaviviruses, alphaviruses, and HCV by 5 - 10 logs in infectious cell culture systems.
  
  
• Linial, Maxine, PhD Training Faculty The main focus is on the foamy viruses (FV), the FV viral replication pathway, its interactions with the host, and viral assembly: to understand which cell proteins are involved in assembly, and the effects of mutations in the Gag protein on this process, the host responses to FV infection, and the ability of the virus to sustain a life-long persistent but nonpathogenic infection. Infection is ubiquitous in non-human primates (NHP) and SIV immunosuppression leads to FV replication in other tissues such as the small intestine, raising the possibility that in NHP, FV could be involved in progression to AIDS.
  
  
• McElrath, M. Juliana, MD, PhD Training Faculty Dr. McElrath’s research focuses on the identification and characterization of cellular immune responses that may provide protection against HIV infection or disease. Particular emphasis lies in defining HIV-specific CD4+ T helper and CD8+ cytotoxic T lymphocyte (CTL) responses in both systemic and mucosal compartments, including 1) how the components of T cell immunity elicited early in HIV-1 infection contribute to the control of HIV-1 disease; 2) whether T cell immune responses play a role in resistance to HIV-1 infection in high-risk persons; 3) the role of antigen-specific mucosal T cells in protecting against HIV-1 exposure; and 4) immune correlates with protection against HIV-1 by vaccination.
  
  
• Mittler, John, PhD Training Faculty Dr. Mittler's laboratory uses concepts and techniques from mathematical ecology and population genetics to study the within-host population ecology and evolution of microorganisms. He uses mathematical models to estimate turnover rates, optimize therapy regimens, and explore hypotheses for HIV-1 pathogenesis in collaboration with Dr. Mullins. His laboratory also conducts experiments with HIV-1, T-cell lines, and macrophages designed to test mathematical models. In collaboration with Dr. Marra, he uses mathematical models to study the compartmentalization of T. pallidum in patients with CNS syphilis.
  
  
• Mullins, James, PhD Training Faculty The Mullins laboratory uses the techniques of molecular, computational and virus biology to provide basic insights into the HIV-human host relationship. Current efforts utilize a variety of techniques to define and understand the implications of HIV's extraordinary evolutionary rate and ensuing genetic diversity. These techniques include virology, molecular biological and statistical analysis (with Dr. Mittler), of nucleotide sequences, and high-throughput array analysis of cellular transcription.
  
  
• Overbaugh, Julie, PhD Training Faculty Dr. Overbaugh’s laboratory focuses on studies of HIV transmission and pathogenesis, using both SIV and HIV to take advantage of experimental and natural infection systems to study the viral genetic determinants of cell-specific replication and pathogenesis. Specific efforts focus on escape variants which replicate to much higher levels in the host, drive disease progression, and are preferentially transmitted from a mother to her infant. Recently, her group has uncovered certain signature sequences among transmitted viruses, and these studies focus on the dynamics of virus populations present early in infection using samples from two Kenyan cohorts: women exposed mucosally to HIV-1 and infants infected through vertical transmission.
  
  
• Schnapp, Lynn MD Training Faculty The main focus of the Schnapp laboratory is on cell-extracellular protein interactions in normal and pathological conditions including interactions of the extracellular environment with HIV in the lung. The lung is an important reservoir of HIV and a site of HIV replication, which results in virus-induced lung injury. We hypothesize that extracellular matrix (ECM) enhances HIV infection within the lung and, conversely, that HIV within the lung alters ECM and contributes to inflammation & fibrosis. We are also interested in the effect of HARRT on the lung milieu and its contribution to matrix remodeling in the lung.
  
  
• Stamatatos, Leo, PhD Training Faculty Research interests include the structure/function analysis of the HIV envelope glycoprotein, HIV-host interactions with emphasis on viral evolution and humoral responses, and HIV vaccine design and testing.
  
  
• Zhu, Tuofu, MD Training Faculty Our laboratory's current area of focus is the pathogenesis of HIV infection, with particular emphasis on the mechanisms of HIV-1 persistence at extraordinarily low levels in vivo. We are devoting considerable effort toward identifying HIV-1 strains that are defective or attenuated, and human genes that protect against or control HIV-1 infection. We also have intense interest in defining the role of CD14+ monocytes in HIV-1 transmission as well as during the very early course of HIV-1 infection. In addition, we use the SIV/macaque model to define events of transmission, and modes of protection against SIV infection..
  
  
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