Research Component 4

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Myelosuppression with granulocytopenia is a common hematologic disorder during HIV infection. Compounding the direct lymphotoxicity of HIV. granulocytopenia is an additional risk factor for secondary infections. Management of granulocytopenia improves survival of patients with HIV infection. Alcohol abuse is a significant co-factor for progression of AIDS. Alcohol injures the bone marrow and impairs myelopoiesis. Antiretroviral therapy (ART) suppresses HIV/SIV replication and has also been shown to ameliorate HIVassociated granulocytopenia. However. ART itself can be myelotoxic. The effects of alcohol on myelosuppression associated with HIV infection and on the protection of ART against granulocytopenia developed during HIV infection are unknown. Our preliminary studies show that SIV infection caused a decrease in granulocyte counts in association with the reduction of CD4+ cell numbers in the circulation. Alcohol consumption aggravated the myelosuppression during SIV infection and exaggerated ART-induced myelotoxicity. Further, alcohol inhibited myelopoietic transcription factor expression by hematopoietic precursors and perturbed the bone marrow environment, inducing a myeloid differentiation block. In this project, we propose to investigate the mechanisms by which alcohol adversely affects hematopoietic stem cell commitment to myeloid lineage development during SIV infection. The experimental focus of this proposal is that alcohol exaggerates myelosuppression during SIV infection and counteracts the protective effects of ART on myelopoiesis. The three Specific Aims are: 1). to test the hypothesis that alcohol suppresses hematopoietic stem cell commitment to granulocyte lineage development during SIV infection; 2). to test the hypothesis that alcohol impairs myeloid differentiation during SIV infection by disrupting the hematopoietic microenvironment; 3: to test the hypothesis that alcohol exaggerates the myelotoxicity of ART. Novel information obtained from this investigation will greatly advance our knowledge concerning the negative impact of alcohol abuse on myelopoiesis in HIV-infected patients. It will also form a foundation for developing effective therapies to treat the combined immunodeficiencies in HIV-infected alcohol abusers.