The candidate completed his training under the mentorship of Dr. Michael Lederman, Professor of Medicine at Case Western Reserve University. The candidate's long-term career goal is to become an independent clinical researcher who will use the clinical trial to answer important questions in HIV disease pathogenesis. The candidate is exploring ways to enhance immune restoration after treatment of HIV infection. The availability of highly active antiretroviral therapy (HAART) has modified dramatically the prognosis of HIV-infected patients. Shortly after the initiation of HAART, patients experience a marked decrease in the incidence of opportunistic complications and death. Immunologically, initiation of HAART is associated with evidence of partial immune restoration. However, there is substantial variability in the magnitude of immune restoration experienced by patients treated with HAART and many patients fail to increase their CD4+ lymphocyte counts significantly. These patients remain at risk for opportunistic infections. After initiation of HAART, there is an initial phase of rapid CD4+ lymphocyte rise thought to be due to lymphocyte redistribution from lymph nodes to the circulation. This phase is followed by a more gradual second phase rise thought to reflect new lymphocyte production. Circulating CD4+ cell numbers may be increased by increasing cellular production or peripheral replication. Although administration of interleukin-2 may increase circulating CD4+ T cell counts, the clinical benefits of CD4+ T cell increases due to interleukin-2 administration are not known. Trials using GM-CSF to simulate T-cell progenitor production are underway, and no applicable methods have been identified to increase thymic function. The investigator proposes an exploratory trial to examine the utility of enhancing cellular redistribution after initiation of HAART by co- administration of prednisone. Since clinical benefit can be demonstrated within weeks after HAART initiation, the candidate proposes that release of trapped immune cells into the circulation and suppression of viral replication may be sufficient to confer clinical benefit. These studies are also designed to examine the mechanisms of prednisone-induced enhancement of cellular restoration. The investigators propose a placebo-controlled study of two weeks of prednisone administration in HIV-infected patients who are about to start HAART. The primary endpoint of the study will be the difference in the magnitude of CD4+ cell rise after 24 weeks of HAART. To ascertain the mechanisms involved in cellular restoration, the investigators will perform careful assays of immune phenotype, adhesion molecule expression, cell cycle progression, and immune function in peripheral blood and lymph node cells at baseline and after initiation of HAART. The magnitude of increase in CD4+ lymphocytes will be correlated with these indices to elucidate the mechanisms of CD4+ lymphocyte rise.
|Lange, Christoph G; Lederman, Michael M; Medvik, Kathy et al. (2003) Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS 17:2015-23|
|Valdez, Hernan; Mitsuyasu, Ronald; Landay, Alan et al. (2003) Interleukin-2 Increases CD4+ lymphocyte numbers but does not enhance responses to immunization: results of A5046s. J Infect Dis 187:320-5|
|Valdez, Hernan (2002) Immune restoration after treatment of HIV-1 infection with highly active antiretroviral therapy (HAART). AIDS Rev 4:157-64|