Immune regulation during the first year of life.
Almost 7 million children under the age of 5 die each year, and most of these deaths are attributable to vaccine-preventable infections. The three infections that cause the most substantial morbidity and mortality are HIV, TB and malaria, and all three disproportionately affect young children. Young infants respond poorly to infections and vaccines. The biology behind these suboptimal responses is the basis for our research. We have demonstrated that healthy infants possess a high frequency of myeloid derived suppressive cells (MDSC). The frequency of these cells gradually declines during the first year of life. Infant MDSC potently suppress T cell proliferation and NK cell killing. The role these cells play in vaccine responses during the first year of life is currently being explored in a longitudinal study of 100 infants through collaboration with Dr. Heather Jaspan in South Africa. The biochemical pathways through which these cells exert immune suppression are currently being examined. Elucidation of these pathways would allow for the development of therapeutics to enhance immune responses to vaccines and infection in early infancy.
Immune function and HIV reservoirs during chronic HIV-infection.
Even though anti-retroviral therapy (ART) significantly reduces viremia to undetectable levels, decreases transmission and stops the progression to HIV disease, immune function is never completely restored and the virus is not cleared. Cessation of treatment results in rapid viral rebound with an accelerated CD4 T cell loss. Why is the viral reservoir not cleared during treatment? We are currently exploring this question from 2 different angles. The first is looking at the nature of the latently infected CD4+ T cell in individuals who started therapy early in infection. What is the specificity of these cells and why can they not be killed by HIV-specific CD8+T responses? The second is looking at the HIV-specific CD8+ T cells questioning why these cells no longer perform their functions (killing HIV-infected cells and, proliferating and secreting cytokines). Uncovering this new knowledge could lead to novel therapeutic interventions, that would render the virus more visible to the immune system as well as target these cells for killing by a highly functional immune response.
CD8+ T cell response in HIV infection.
Although identified over 30 years ago, human immunodeficiency virus type 1 (HIV-1), commonly known as HIV, continues to be a devastating epidemic throughout the United States and the world claiming for more than 39 million lives so far. The estimated 35 million people living with HIV-1 at the end of 2013, the 2.1 million new infections per year and the1.8 million deaths every year, underscore the urgency to develop a safe, effective and accessible prophylactic vaccine. Even with the introduction of antiretroviral therapy, this disease continues to be a major public health problem today. Although anti-retroviral therapy is known to significantly reduce viremia to undetectable levels, there are a rare group of HIV infected individuals (known as Long-Term Non-Progressors; LTNPs) who can control viremia without treatment. What allows these individuals to control infection? The mechanisms/host factors leading to differences in the ability of individuals to control infection are not entirely understood. HIV work in the Horton Laboratory primarily focuses on two principal areas of HIV research: 1) Identifying HIV-1 specific CD8+ T cell responses during early and chronic infection and 2) Understanding mechanisms/factors that enable some rare HIV infected individuals to control in HIV infection. Collectively, understanding mechanisms of such phenomenon will likely provide insight for development of therapeutic interventions and enhance rational vaccine design.
Role of Suppressive cells during HIV infection.
Regulatory T cell-(Tregs)mediated suppression is increased during chronic HIV-1 infection. HIV-specific CD8+ T cells become tolerant in that they do not proliferate or kill HIV infected target cell as efficiently as virus-specific T cells from other non-persistent viral infections (e.g. Influenza). We have demonstrated that Tregs differentially suppress CD8+ T cell responses during HIV infection. CD8+ T cells restricted by certain HLA alleles like HLA-B27 and HLA-B57 are resistant to Treg-mediated suppression compared to CD8+ T cell responses restricted by other alleles, e.g. A*02/A*03 alleles. The mechanism(s) leading to HIV-specific CD8+ T cell tolerance are not entirely known. Understanding the suppressive mechanisms mediated by Tregs would allow us to develop interventions that enhance the natural or vaccine-induced ability of CD8+ T cells to eradicate HIV-infected cells.
Myeloid Derived suppressor cells are also increased during HIV-infection. As these cells are potent inhibitors of T cell and NK cell responses, their role during the course of HIV-infection and treatment is being studied. These cells increase soon after HIV-infection and persist at high frequency during the course of chronic infection, despite antiretroviral therapy. The role these cells play in the immune dysfunction during HIV infection is currently being studied.
As part of the CFAR Cellular and Immunology Core, our laboratory provides services and training to the HIV research community in cellular immunology and vaccine research.