Research Component 4

粒细胞减少伴骨髓抑制是HIV感染期间常见的血液学疾病。加重了HIV的直接淋巴毒性。粒细胞减少症是继发感染的另一个危险因素。粒细胞减少症的治疗可提高HIV感染患者的生存率。酗酒是艾滋病发展的重要辅助因素。酒精会损伤骨髓，阻碍骨髓生成。抗逆转录病毒治疗（ART）抑制HIV/SIV复制，也已被证明可以改善HIV相关的粒细胞减少症。然而。抗逆转录病毒治疗本身可能具有骨髓毒性。酒精对与艾滋病毒感染相关的骨髓抑制的影响以及对抗逆转录病毒治疗对艾滋病毒感染期间出现的粒细胞减少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的减少与循环中CD4+细胞数量的减少有关。酒精摄入加重了SIV感染期间的骨髓抑制，并夸大了art诱导的骨髓毒性。此外，酒精通过造血前体抑制骨髓转录因子的表达，扰乱骨髓环境，诱导骨髓分化阻滞。在这个项目中，我们建议研究酒精在SIV感染期间对造血干细胞对髓系谱系发育的不利影响的机制。这一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。三个特定目的是：1)验证酒精在SIV感染期间抑制造血干细胞对粒细胞谱系发育的承诺的假设；2).验证酒精通过破坏造血微环境影响SIV感染期间骨髓分化的假设；3：检验酒精夸大抗逆转录病毒治疗骨髓毒性的假设。从这项调查中获得的新信息将大大提高我们对酒精滥用对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感染艾滋病毒的酗酒者的综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.