This application outlines a 4 year plan for the development of a career in medical science within the Division of Infectious Disease at the UCLA School of Medicine. Its Principal Investigator has completed training in Internal Medicine and graduate work in the field of medical virology. As a fellow in the Division of Infectious Diseases and member of the UCLA Subspecialty Training and Advanced Research (STAR) program she now details a plan to expand her knowledge and skills in the area of medical virology and immunology in order to become an independent investigator. The proposed program will be carried out under the mentorship of Dr. Otto Yang, a very well-respected, successful member of both the Division of Infectious Diseases and Microbiology, Immunology, and Medical Genetics. Dr. Yang has successfully supervised post-doctoral fellows and graduate students and is an expert in the field of HIV immunology. In particular his research group is a leader in the study of cytotoxic T lymphocyte (CTL) responses to HIV-1 infection. The UCLA research community with its numerous resources and opportunites will provide an excellent environment for the completion of the proposed research plan. The plan focuses on investigating factors influencing the HIV-1 accessory protein Nefs ability to mediate evasion of CTL immune responses. Previous studies by Dr. Yang and others showed that Nef down-regulates MHC Class I on infected cells making them less sensitive to killing by CTLs.
The specific aims to be addressed include the following: 1. What factors affect the influence of Nef-mediated MHC-I downregulation on HIV-1 resistance to CTL? 2. What are the impacts of Nef-specific and non-Nef-specific CTLs on Nefs MHC down-regulatory function? 3. What are the relative selective pressures exerted by Nef-specific and non-Nef-specific CTLs on Nef sequence evolution? A combination of in vitro and in vivo methods will be utilized in order to explore the balance between host immune forces which favor the loss of Nefs function and viral forces which favor the retention of Nefs ability to down-regulate MHC I and thus evade CTL killing. The results of these studies are anticipated to further our knowledge of how the immune system works to control HIV-1 infection. This knowledge will help in the ongoing quest for an effective vaccine against HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI068449-03
Application #
7384404
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Young, Janet M
Project Start
2006-03-01
Project End
2010-02-27
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$63,458
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lewis, Martha J; Lee, Patricia; Ng, Hwee L et al. (2012) Immune selection in vitro reveals human immunodeficiency virus type 1 Nef sequence motifs important for its immune evasion function in vivo. J Virol 86:7126-35
Ali, Ayub; Realegeno, Susan; Yang, Otto O et al. (2009) Simultaneous assessment of CD4 and MHC-I downregulation by Nef primary isolates in the context of infection. J Virol Methods 161:297-304
Lewis, Martha J; Balamurugan, Arumugam; Ohno, Ayako et al. (2008) Functional adaptation of Nef to the immune milieu of HIV-1 infection in vivo. J Immunol 180:4075-81
Balamurugan, Arumugam; Lewis, Martha J; Kitchen, Christina M R et al. (2008) Primary human immunodeficiency virus type 1 (HIV-1) infection during HIV-1 Gag vaccination. J Virol 82:2784-91