The Retroviral Diseases Section of the HIV and AIDS Malignancy Branch conducts translational clinical and laboratory research aimed at the development of novel therapies for HIV infection and AIDS- related malignancies. It also conducts laboratory research focused on an understanding of these diseases. During the past year, the group has investigated the role of conserved cysteines at positions 67 and 95 on the activity of HIV protease. We have found that glutathiolation of Cys 95 abolishes HIV-1 protease activity, while glutathiolation of Cys 67 can enhance activity. HIV virions with mutations of Cys 95 and Cys67 have been generated and we are studying the effects that these mutations have on the fitness of HIV under varying conditions. We are exploring the regulation of HIV-2 protease and have preliminary results showing that a methionine in position 95 of HIV-2 acts in a way similar to the cysteine in position 95 of HIV-1 in terms of regulating the protease activity. We are in the process of extending these observations to the proteases of other retroviruses. Also, we are attenpting to design inhibitors of HIV protease that act through binding to these conserved cysteines. Other laboratory studies have involved a study of the differential ability of protease inhibitors in monocytes and lymphocytes and the mechanisms that might cause these differences. We have also continued the investigation of the combined activity of a newly discovered herpesvirus, called Kaposis sarcoma- associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), and HIV in the pathogenesis of Kaposis sarcoma (KS). We are also conducting several clinical trials to evaluate novel therapies for Kaposis sarcoma. We have recently obtained preliminary results indicating that the anti-angiogenesis agent thalidomide is active in a subset of patients with Kaposis sarcoma. We are also studying IL-12 for possible activity in Kaposis sarcoma and also the anti- herpes drug cidofovir and its effect on the expression of KSHV-related genes in KS. We are also studying infusional chemotherapy and IL-12 as therapy for AIDS- associated lymphoma. In regard to anti-HIV therapy, we have initiated clinical trials of the dideoxynucleoside reverse transcriptase inhibitor beta-fluoro-dideoxyadenosine (FddA) in adults, both alone and in a combination regimen. This drug is active in vitro even against strains of HIV that are resistant to a number of other dideoxynucleosides. We are planning a study of this agent used in combination with hydroxyurea, which potentiates the activity of F-ddA in vitro by increasing the intracellular ratio of F-ddA-triphosphate to ddATP. In addition, a clinical trial is under way to study two HIV envelope peptide vaccines in HIV-infected patients in combination with highly active antiretroviral therapy. Preliminary results indicate that the vaccine can boost proliferative T cell responses against HIV in a majority of patients. The project is 100% AIDS research (about 50% is both AIDS and cancer). - AIDS, herpesviruses, HIV, IL-, Kaposi's sarcoma, lymphoma, proteases, reverse transcriptase, vaccines, Kaposi's sarcoma associated herpesvirus, - Human Subjects

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National Cancer Institute (NCI)
Intramural Research (Z01)
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National Cancer Institute Division of Clinical Sciences
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Morrow, Matthew; Valentin, Antonio; Little, Richard et al. (2008) A splenic marginal zone-like peripheral blood CD27+B220- B cell population is preferentially depleted in HIV type 1-infected individuals. AIDS Res Hum Retroviruses 24:621-33
O'Mahony, D; Gandjbakche, Ah; Hassan, M et al. (2008) Imaging techniques for Kaposi's sarcoma. J HIV Ther 13:65-71
Davis, David A; Singer, Kathleen E; Reynolds, Irene P et al. (2007) Hypoxia enhances the phosphorylation and cytotoxicity of ganciclovir and zidovudine in Kaposi's sarcoma-associated herpesvirus infected cells. Cancer Res 67:7003-10
Marshall, Vickie; Parks, Thomas; Bagni, Rachel et al. (2007) Conservation of virally encoded microRNAs in Kaposi sarcoma--associated herpesvirus in primary effusion lymphoma cell lines and in patients with Kaposi sarcoma or multicentric Castleman disease. J Infect Dis 195:645-59
Bernstein, Wendy B; Little, Richard F; Wilson, Wyndham H et al. (2006) Acquired immunodeficiency syndrome-related malignancies in the era of highly active antiretroviral therapy. Int J Hematol 84:3-11
Haque, Muzammel; Wang, Victoria; Davis, David A et al. (2006) Genetic organization and hypoxic activation of the Kaposi's sarcoma-associated herpesvirus ORF34-37 gene cluster. J Virol 80:7037-51
Semenova, Elena A; Johnson, Allison A; Marchand, Christophe et al. (2006) Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by alpha-hydroxytropolones. Mol Pharmacol 69:1454-60
Little, Richard F; Pluda, James M; Wyvill, Kathleen M et al. (2006) Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma. Blood 107:4650-7
Davis, David A; Singer, Kathleen E; De La Luz Sierra, Maria et al. (2005) Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1alpha in the circulation. Blood 105:4561-8
Yarchoan, Robert; Tosato, Giovanna; Little, Richard F (2005) Therapy insight: AIDS-related malignancies--the influence of antiviral therapy on pathogenesis and management. Nat Clin Pract Oncol 2:406-15; quiz 423

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