Infection by the human immunodeficiency virus (HIV) severely impacts the human immune system. With the advent of highly active antiretroviral therapy (HAART), the lives of HIV infected individuals have much improved. However, immune impairment still persists. While AIDS-related malignancies have decreased significantly, the occurrence of non-AIDS related cancers is higher in HIV infected individuals versus the general population. The reasons for this phenomenon are still under investigation. However, studies have implicated the loss of CD4 T cells and the chronic immune activation observed in HIV patients as potential factors that can impact the function and maturation of cytotoxic T cells (CTL), the effector arm of our immune system. Such outcome will, in turn, influence the ability of the host to mount effective immune responses against other pathogens and cancers. In this proposal, we aim to examine the impact of HIV infection on the responses elicited by tumor specific CTLs. We have constructed a modified version of the BLT humanized mouse model where we generated functional melanoma specific CD8 T cells from genetically engineered human progenitors. These mice will be infected with HIV and then challenged with melanoma tumors to assess the quality of anti-melanoma immune responses.
In Specific Aim #1, we propose to in vivo monitor tumor regression and transgenic CTL maturation in the context of HIV infection. Furthermore, we will isolate the melanoma specific CTL and further examine their functionality.
In Specific Aim #2, we will determine if the administration of HAART remedies the observed defects caused by HIV infection. In both aims, collected immune monitoring data will be further analyzed to further characterize the impact of HIV infection on the transgenic CTL. Finally, for both aims, transgenic CTLs will be isolated and used for microarray analysis to study any gene expression changes due to HIV infection. The proposed studies will expand our knowledge on the function of CTLs within the context of HIV infection. Such knowledge is essential, as it will pave the way for the development of improved immune based interventions for HIV infected individuals.

Public Health Relevance

Non-AIDS related malignancies are on the rise in HIV-infected individuals on antiretroviral therapy. Cytotoxic T cells (CTL), the effector arm of our immune system, play an important role in controlling infection and cancer. In this proposal, which focuses on the impact of HIV infection on cytotoxic T cell function, the goals are to examine in vivo how HIV infection impairs CTL function and whether antiretroviral therapy can reverse the defect.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Sanders, Brigitte E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Saleh, Suha; Lu, Hao K; Evans, Vanessa et al. (2016) HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-?B. Retrovirology 13:49
Burke, Bryan P; Levin, Bernard R; Zhang, Jane et al. (2015) Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector. Mol Ther Nucleic Acids 4:e236
McCracken, Melissa N; Vatakis, Dimitrios N; Dixit, Dhaval et al. (2015) Noninvasive detection of tumor-infiltrating T cells by PET reporter imaging. J Clin Invest 125:1815-26