Training

STD/AIDS Research Training Fellowship Program

Viral STD Research Track

Denise A. Galloway, Ph.D., Director; Larry Corey, MD; James I. Mullins, Ph.D., 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).

Pre-doctoral students are PhD candidates in Microbiology, Pathology, Pathobiology or in Molecular and Cellular Biology. Students may apply for this track once they have completed a year of course work in relevant disciplines and three lab rotations before joining a lab of a faculty member in this track (or two years of medical school for our MD/PhD students), and select a thesis project. A thesis committee is set up in year two, containing several Viral STD track faculty, who monitor the student's progress yearly, suggest appropriate 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 Viral STD Track faculty members for post-doctoral positions, and like the pre-doctoral 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. They typically stay in this position for 3-4 years before seeking an independent position. MD fellows have completed a residency and enter one of the Clinical Fellowship programs at UW, particularly Infectious Diseases, but also in other specialties. They participate in the same courses and meetings as the PhD fellows, and more often audit the didactic courses to update their basic science knowledge. For those with minimal research experience the training period in the laboratory is often longer, approx. 5 years, and will include both training grant support and other awards such as KO8s from the NIH or HHMI physician scientist grants. Learning to write for these grants is a key part of training for the Fellows. The MD fellows also develop their clinical skills in the management of STDs and HIV infection.

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), co-organized by Drs. Linial and Galloway. 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 post-doctoral 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: 25 training faculty and 20 resource faculty participate in this track.

• Research Training Opportunities: A short synopsis of the research of the 19 senior and 5 of the new training faculty is provided below:
  
  
• Corey, Larry, MD. Dr. Corey's research spans herpes group infections, the pathogenesis of primary HIV infection, and HIV vaccine development. The genital HSV program involves clinical investigations of HSV reactivation and transmission; laboratory-based studies on the cellular immunology of HSV, studies of HSV-HIV interactions, and development of an HSV vaccine. The HHV-8 program studies transmission and mucosal shedding, and interactions between HHV-8 and epithelial cells. Dr. Corey heads the NIAID-supported HIV Vaccine Trials Network (HVTN), which offers training opportunities for postdoctoral fellows interested in vaccine biology or clinical trials methodology.
  
  
• Galloway, Denise, PhD. The Galloway laboratory investigates the natural history of genital HPV infection and the role of HPV in anal and genital neoplasias, with emphases on how HPV oncoproteins E6 and E7 disrupt cell proliferation, and on use of serology to better understand the natural history of genital HPV, mapping immunoreactive epitopes on HPV capsids, and addressing risk factors associated with progression to cancer among HPV-infected women.
  
  
• Mullins, James, PhD. The Mullins laboratory uses techniques of molecular, computational and virus biology to provide basic insights into the HIV-human host relationship, linked to in vivo analyses of biological activity. The evolution of HIV is being studied within and between hosts, with the potential for deriving broadly reactive immunogens for vaccine development, for refinement of therapies, and for understanding of the epidemiology of HIV transmission and spread. Expression array technology is used to understand the cellular response to infection and expression of viral proteins.
  
  
• Ashley Morrow, Rhoda, PhD. Dr. Morrow' research involves the development and application of novel diagnostic tests for human viral pathogens, and analysis of local antibody responses to sexually transmitted viruses, including HSV-1, HSV-2, HHV-6, and HHV-8, among others, in cohorts in the US and Africa.
  
  
• Collier, Ann, MD. Dr. Collier heads the UW ACTG and directs several clinical trials of HIV therapy. Multiple therapies under investigation, include reverse transcriptase inhibitors, protease inhibitors, and HIV entry inhibitors. Collaborators include Dr. Jorge Sanchez, co-PI with Dr. Collier of our new NIH International AIDS Clinical Trials Unit in Lima, Peru.
  
  
• Coombs, Robert, MD, PhD. Dr. Coombs studies the pathogenesis of HIV-1 and the quantification of viral load in the setting of therapeutic clinical trials involving both adult and pediatric HIV-1 infected subjects. Of interest are markers of infectivity when viral RNA levels are suppressed with effective antiretroviral therapy. His research elucidates the shedding of HIV-1 in the male and female genital tracts; and the regulation of HIV-1 shedding by CMV and by immunological mechanisms.
  
  
• Emerman, Michael, PhD. Dr. Emerman is studying the molecular basis of action of an HIV-encoded protein Vpr, to understand how and why HIV interferes with the host cell cycle; and how HIV is able to infect non-dividing cells such as terminally differentiated macrophages, by gaining nuclear entry independent of the cell cycle.
  
  
• Frenkel, Lisa, MD. Dr. Frenkel directs the UW Pediatric ACTG. Her research examines HIV-1 evolution and selection of drug-resistant virus during effective HAART, in blood and in the female genital tract; evaluation of HIV-1 specific immunization of infants by breastfeeding from infected mothers during nevirapine chemoprophylaxis, defining the selection and persistence of nevirapine-resistant HIV-1 by peripartum chemoprophylaxis regimens; development of rapid and inexpensive tests for drug-resistant HIV-1 suitable for use in resource-poor settings; and defining HIV-1 drug resistance in various settings.
  
  
• Greenberg, Philip, MD. The Greenberg laboratory is developing cellular and molecular strategies to modulate T-cell function for the purpose of treating viral and malignant diseases. Clinical trials being developed will employ genetically-modified autologous HIV-specific T-cell clones. The laboratory is also evaluating novel vaccine strategies that improve antigen presentation or enhance T-cell activation for prevention and/or treatment of SHIV infection in macaques.
  
  
• Gretch, David, MD, PhD. Dr. Gretch conducts systematic longitudinal investigation of hepatitis C virus replication, immune responses, quasispecies formation and disease progress in three well-defined human cohorts: 1) the Alaskan Native American ANA cohort; 2) the HALT-C trial; and 3) over 500 HCV-infected liver transplant recipients. Dr. Gretch recently received NIH funding to study the impact of HIV infection in the pathogenesis of HCV-induced hepatitis.
  
  
• Haigwood, Nancy, PhD. Dr. Haigwood studies HIV pathogenesis, perinatal transmission, and vaccine design, using nonhuman primates to determine the effectiveness of novel therapies and vaccines in viral challenge models. Dr. Haigwood's laboratory has led efforts to define the role of neutralizing antibodies in protection, and to develop novel vectors for antigen delivery and induction of immune responses.
  
  
• Hooton, Thomas, MD. Dr. Hooton directs the HIV/AIDS clinic at Harborview. His research concerns optimizing the prevention of opportunistic infections in AIDS Clinical Trial Group (ACTG) studies, treatment of metabolic dysfunction during antiretroviral therapy, and adherence in HIV treatment.
  
  
• Katze, Michael, PhD. Dr. Katze examines mechanisms used by viruses (HCV, HIV-1, and SIV) to avoid the interferon-mediated antiviral response, and to take over cellular protein synthesizing machinery. The lab also uses functional genomics, including cDNA microarrays and proteomics, to study changes in cellular gene expression and protein production that occur in response to virus infection. A bioinformatics group has been assembled to aid in interpreting data generated for these analyses.
  
  
• Koelle, David, MD. Dr. Koelle is identifying HSV antigens recognized by human T-cells and assessing their immunodominance in HSV-infected person with defined disease activity; focus is on endogenous synthesis of CD8+ CTL target epitopes; T-cell homing to the skin and genital tract (he has found that HSV-2-specific CD8+ T-cells use a specific adhesion molecule, CLA, to home to the skin; and the immunogenicity of a phase I HSV-2 vaccine.
  
  
• Krieger, John, MD. Dr. Kreiger studies of the etiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); HIV load and transmission of HIV in semen, and the localization and replication of HIV in the male urogenital tract.
  
  
• Lagunoff, Michael, PhD. Dr. Lagunoff studies the molecular virology of and tumor induction by HHV-8. The laboratory focuses on how viral signaling genes might lead to viral pathogenesis, including the K1 gene, which causes constitutive host cell signal transduction through a variant immunoreceptor tyrosine-based activation motif (ITAM).
  
  
• Lingappa, Jaisri, MD, PhD. Dr. Lingappa uses a novel cell-free system to dissect biochemical events involved in HIV capsid assembly, to show that assembly proceeds through post-translational assembly intermediates and requires energy substrates. She has identified a nucleotide-binding host factor (HP68) essential for post-translational events in capsid formation, and is studying how HP68 acts during HIV-1 capsid formation, and whether other viruses utilize HP68 during their assembly.
  
  
• Linial, Maxine, PhD. The Linial lab is interested in retroviral assembly and host-cell interactions. Retroviruses package two copies of genomic RNA into particles. Genomic RNA has all the hallmarks of cellular mRNA and must be recognized by viral protein from the pool of normal cellular messages.
  
  
• McElrath, M. Juliana, MD, PhD. Dr. McElrath is characterizing cellular immune responses that may protect against HIV infection or disease, defining HIV-specific T helper and CD8+ cells cytotoxic T lymphocyte (CTL) responses in both systemic and mucosal compartments. Questions under investigation include: 1) What components of T cell immunity elicited early in HIV-1 infection contribute to the control of HIV-1 disease, and how is this influenced by HAART? 2) Do T cell immune responses play a role in resistance to HIV-1 infection in persons repeatedly exposed by sexual contact? 3) Do antigen-specific mucosal T cells protect against HIV-1 exposure? 4) What elements of immunity correlate with protection against HIV-1 infection by vaccination?
  
  
• Mittler, John, PhD. Dr. Mittler's laboratory uses concepts and techniques from mathematical ecology and population genetics to study 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; and he is initiating experiments with HIV-1 and T-cell lines designed to test assumptions of mathematical models.
  
  
• Overbaugh, Julie, PhD. Dr. Overbaugh studies how retroviruses disrupt T-cell function and cause disease in the host. Her research involves both SIV and HIV, in comparative studies of the viral genetic determinants of cell-specific replication and pathogenesis. She has found that changes in the SIV envelope during the course of disease alter the ability of host neutralizing antibodies to recognize and contain the virus. Her studies involve two Kenyan cohorts: women exposed sexually to HIV-1; and infants infected through vertical transmission.
  
  
• Rose, Timothy, PhD. The Rose laboratory studies DNA herpesviruses implicated in cellular transformation and tumor induction, and the host and viral proteins and cytokines which mediate these effects. They have discovered two new herpesviruses in macaques associated with a KS-like malignancy, retroperitoneal fibromatosis, which like AIDS-KS is also associated with a retrovirus infection; and have participated in discovery and characterization of a human cytokine, oncostatin M (OSM), the major autocrine/paracrine growth factor for KS.
  
  
• Stamatatos, Leo, PhD. Dr. Stamatatos' HIV envelope structure/function analyses involve introducing specific modifications, such as deglycosylations and hypervariable loop-deletions in the HIV envelope, to examine the effect on the viral phenotype, especially neutralization-susceptibility.
  
  
• Zhu, Tuofu, MD. Dr. Zhu has shown that HIV-1 replicates in CD14+ monocytes in vivo, and is now defining the roles of CD14+ monocytes in HIV-1 infection through study of viral genotypes in purified CD14+ monocytes and CD4+ T lymphocytes from drug-naïve individuals. Further studies examine the role of CD14+ monocytes as a source of virus that will dominate in the later stage of HIV-1 infection.
  
  
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