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 previously found that glutathiolation of Cys 95 (in the dimer interface) 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 have recently found that nearly all retroviral proteases are regulated by oxidizable amino acids at the dimer interface and that in the case of HIV-1, this occurs by interfering with dimer formation. HIV from some patients who have developed resistance to protease inhibitors have been also found to develop a mutation in Cys95, and we are trying to understand the evolutionary pressures leading to this mutation. This work on HIV protease has identified the dimer interface as a potential therapeutic target, and we are attempting to design inhibitors of HIV protease that act as this site. We are also investigating the role of a newly discovered herpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), in the pathogenesis of Kaposi's sarcoma (KS). We have found that hypoxia can activate latent KSHV to undergo lytic replication. We have found evidence that three genes of KSHV are specifically upregulated by hypoxia: Rta, ORF34, and viral Bcl-2. In one case, we have identified a hypoxia responsive element (HRE) in the promoter region that is upregulated by hypoxia inducible factor (HIF). We are also conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma with a focus on anti-angiogenesis approaches. We have recently found that the anti-herpes drug cidofovir, which has in vitro activity against KSHV, does not induce remissions in patients with KS. We have found preliminary evidence that the cytokine IL-12 has long-acting activity in Kaposi's sarcoma have initiated a trial to study the combination of IL-12 and a liposomal anthracycline in patients with advanced KS. We are also studying antibody to VEGF as a therapeutic agent in KS and are planning a trial to study several pilot therapies for Castleman's disease. We are also studying infusional chemotherapy as therapy for AIDS-associated lymphoma in collaboration with the Experimental Immunology and Transplantation Branch. In regard to anti-HIV therapy, we are initiating a clinical trial to explore whether specific immunity can be developed to a cruical sequence in reverse transcriptase.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006737-12
Application #
6947459
Study Section
(HAMB)
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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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