Research Component 4

骨髓抑制伴粒细胞减少是HIV感染时常见的血液系统疾病。加剧了艾滋病病毒的直接光毒性。粒细胞减少是继发感染的另一个危险因素。粒细胞减少症的管理提高了HIV感染患者的生存率。酒精滥用是艾滋病进展的重要辅助因素。酒精会损伤骨髓，损害骨髓生成。抗逆转录病毒疗法（ART）抑制HIV/SIV复制，并且还显示出改善HIV相关的粒细胞减少症。然而. ART本身可能具有骨髓毒性。酒精对与HIV感染相关的骨髓抑制的影响以及ART对HIV感染期间发生的粒细胞减少症的保护作用尚不清楚。我们的初步研究表明，SIV感染引起粒细胞计数减少，与循环中CD 4+细胞数量减少有关。饮酒加重了SIV感染时的骨髓抑制，并加重了ART诱导的骨髓毒性。此外，酒精抑制造血前体细胞的骨髓转录因子表达，扰乱骨髓环境，诱导骨髓分化阻滞。在这个项目中，我们建议调查的机制，酒精不利地影响造血干细胞的承诺，在SIV感染的髓系发育。该建议的实验重点是酒精在SIV感染期间夸大骨髓抑制，并抵消ART对骨髓生成的保护作用。三个具体目标是：（1）。检验酒精在SIV感染期间抑制造血干细胞向粒细胞谱系发育定型的假设; 2）.检验酒精通过破坏造血微环境损害SIV感染过程中骨髓分化的假设; 3：检验酒精夸大ART的骨髓毒性的假设。从这项调查中获得的新信息将大大推进我们对酒精滥用对HIV感染患者骨髓生成的负面影响的认识。它还将为开发有效疗法以治疗受艾滋病毒感染的酗酒者的联合免疫缺陷奠定基础。

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.