Savita Pahwa, M.D.
Professor of Microbiology and Immunology, Director of CFAR
Room 712 (office), 708 (lab) Batchelor Children's Research Institute
Our group is interested in the immunopathogenesis of HIV infection for the understanding of the nature and mechanisms of immune dysfunction in HIV infected pediatric and adult patients. We hope that our studies will help in developing strategies for immune reconstitution, and for aborting disease progression in HIV infected subjects.
1. Memory CD8 T cells in HIV Disease. CD8 T cells can be divided into four broad groups based upon phenotypic and functional characteristics, and are termed as na´ve, central memory, peripheral or effector memory, and effector T cells. We are investigating functional attributes of these subsets to understand the relevant CD8 T cell population that correlates with immune protection in HIV infection. We wish to understand why defects of HIV-specific memory T cells persist in patients despite treatment with antiretroviral drugs. We plan to determine the frequency, function and regulation of long-term memory T cells for HIV; study their relationship with cytokine receptor expression and cytokine responsiveness; and understand factors influencing their maturation into effector cells. If we can successfully monitor long-term memory T cells, our studies will facilitate the development of optimal vaccine strategies for HIV.
2. Aberrant Immune Activation. Ample evidence exists for excessive immune activation in HIV disease, and is characterized by the presence of increased proportions of CD8 T cells that express activation markers CD38 and HLA-DR. Heightened immune activation has been found to be deleterious to the host, and to correlate more strongly with CD4 cell loss than levels of plasma virus load. We and others have reported exaggerated apoptosis of CD4 and CD8 T cells associated with excessive immune activation. We are investigating the mechanisms of aberrant immune activation and strategies to dampen it. Specifically, we are interested in investigating the role of inflammatory cytokines, HIV gene products, role of macrophages/innate immune cells, and regulatory T cells in this process. Towards this goal, we are developing assays that can differentiate between an inflammatory CD8 T cell response from a cytotoxic antiviral response.
3. Immune Reconstitution in HIV disease. The severe immune deficiency of HIV disease is characterized by a quantitative and qualitative deficiency of CD4 T cells. Recently, defects of cells of the innate immune system, such as plasmacytoid and myeloid dendritic cells have been described in HIV infected patients, and in normal cells that are infected with HIV in vitro. We will investigate how abnormalities of the innate immune system lead to defects of the adaptive immune system, and devise intervention strategies to manipulate the immune system for enhancing immune responses, including T helper cell function. T cells from thymus and cord blood will be studied for investigating activation and maturation of na´ve T cells. Subjects in clinical trials with antiretroviral drugs and cytokine therapies (IL-2, IL-7) will be evaluated for immune reconstitution.
Patients: We have access to a diverse group of well-characterized patients who differ in stage of HIV disease, (acute versus chronic infection), rate of disease progression (rapid versus slow progression and non progression), age (children, adolescents, adults), and mode of acquisition of HIV (trans-placental, intravenous substance abuse, sexual transmission). Many of these patients are in clinical trials with investigational antiretroviral medications, and include patients in the NIH sponsored pediatric and adult ACTG (AIDS Clinical Trials Group). Our program has one of the five national NIH-designated Immunology Support Laboratories that specifically conduct immunological investigations in patients from the ACTG.
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Pahwa S, Pahwa R, Saxinger C, Gallo RC, and Good RA. Influence of human T-Lymphotropic virus/lymphadenopathy-associated virus on functions of human lymphocytes: Evidence for immunosuppressive effects and polyclonal B-cell activation by banded viral preparations. Proc Natl Acad Sci. 82:8198-8202, 1985.
Oyaizu N, Chirmule N, Kalyanaraman S, Hall, WW, Pahwa R, Schuster M, Good RA, and Pahwa S. Human Immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+T lymphocytes by inhibiting interleukin 2 mRNA. Proc. Natl. Acad. Sci. 87:2379-2383, 1990.
Oyaizu N, McCloskey T, Chirmule N, Yagura H, Kalyanaraman VS, Coronesi M, and Pahwa S
. Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals. Blood 82:3392-3400, 1993
Adachi Y, Oyaizu N, Than S, McCloskey TW, and Pahwa S
. IL-2 Rescues in vitro Lymphocyte Apoptosis in Patients with HIV Infection: Correlation with its Ability to Block Culture-induced Down-Modulation of Bcl-2. The Journal of Immunology. 157:4184-93, 1996
Chavan S, Bennuri B, Kharbanda, M Chandrasekaran A, Bakshi S and Pahwa S
. Evaluation of T cell receptor gene rearrangement excision circles after antiretroviral therapy in children infected with human immunodeficiency virus. J Inf Diseases 183:1445-1454, 2001
Haridas, V, McCloskey TW, Pahwa R and Pahwa S. Discordant expression of perforin and granzyme A in total and HIV-specific CD8 T lymphocytes of HIV infected children and adolescents. AIDS 17:2313-22, 2003.