IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV 1 INFECTION

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The purpose of this project is to characterize the immunologic abnormalities associated with HIV infection, develop immunologic approaches to the therapy of patients with HIV infection and utilize these immune based therapies as tools for obtaining additional insights as to the pathophysiologic mechanisms present in patients with HIV infection. HIV infection is associated with a progressive decline in immune function as evidenced by a progressive decline in the number and the repertoire of the CD4 T lymphocyte pool of the immune system. This fundamental defect in the immune system was identified before the identification of HIV as the etiologic agent of AIDS. This project is aimed at reversing this process through the use of interleukin-2 (T cell growth factor) to increase the number of CD4 T lymphocytes in the setting of HIV infection. A series of randomized studies have been carried out that have established this as a feasible method for increasing the CD4 count in patients with HIV infection; these studies have been extended to optimize the dosing regimens for maximal immunologic and virologic benefit while minimizing side effects. Cohorts of patients are being followed who have received this treatment for periods that now extend beyond 6 years. The laboratory is now engaged in a series of collaborations with our extramural colleagues, both in the US and abroad, to extend this approach to phase III trials. The potential of the T cell limb of the immune system to respond to different antigens is defined through the diversity of the T cell repertoire. As noted above, HIV infection leads not only to a decrease in the total number of CD4 T lymphocytes, but also to a decline in the diversity of the T cell repertoire. In an attempt to expand the ability of the T cell repertoire to recognize and respond to HIV infected cells, work is ongoing under this project to utilize the tools of gene therapy to create chimeric human T cells that express not only their native receptor but also a second receptor with specificity for HIV. The feasibility of this approach for the treatment of patients with HIV infection is being examined utilizing syngeneic twin pairs discordant for HIV infection, in which cells from the healthy twin are removed, genetically modified and then infused to the HIV-infected twin. In addition, studies are underway examining the potential of DNA vaccination as a means of eliciting specific immunity to HIV. While HIV infection elicits the production of antibodies, these antibodies appear incapable of exerting a substantial effect on the course of HIV infection. As new knowledge is derived regarding the structure-function relationships of the HIV envelope protein, new epitopes, shielded from the immune system in vivo, are being identified as potential targets for antibody therapy. Through the generation of random recombinatorial libraries, an anti-gp120 antibody has been identified that may be of therapeutic value. Clinical trials using this antibody will begin within the next year. The T cell pool undergoes constant change as new cells are created through the division of existing cells, as stem cells differentiate through a thymic environment, and as cells die. In the setting of HIV infection these changes are pronounced due to the inflammatory and destructive influences associated with this disease. To gain a better understanding of T cell dynamics in the setting of HIV infection it has been necessary to obtain a better understanding of these processes in healthy individuals. A series of studies are underway to examine rates of T cell turnover in vivo in humans utilizing the complementary approaches of bromodeoxyuridine and deuterated glucose labeling to be able to measure individual cell and pool turnover rates.