Research Component 4

骨髓抑制伴粒细胞减少是HIV感染过程中常见的血液病。混合了艾滋病毒的直接淋巴毒性。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感染者的存活率。酗酒是艾滋病进展的一个重要辅助因素。酒精会损害骨髓，损害骨髓生成。抗逆转录病毒疗法(ART)抑制HIV/SIV复制，也被证明可以改善HIV相关性粒细胞减少症。然而。ART本身可能具有骨髓性毒性。酒精对HIV感染引起的骨髓抑制的影响以及ART对HIV感染期间出现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感染引起的粒细胞数量减少与循环中的CD4+细胞数量减少有关。酒精摄入加重了SIV感染时的骨髓抑制，并夸大了ART诱导的骨髓毒性。此外，酒精通过造血祖细胞抑制骨髓细胞转录因子的表达，扰乱骨髓环境，导致髓系分化受阻。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发育的负面影响的机制。这项提议的实验重点是酒精在SIV感染期间夸大了骨髓抑制，并抵消了ART对骨髓生成的保护作用。三个具体目标是：1)。2)验证酒精抑制SIV感染期间造血干细胞对粒系发育的承诺的假说；验证酒精通过破坏造血微环境在SIV感染过程中损害髓系分化的假说；3：检验酒精夸大ART的骨髓毒性的假说。从这项调查中获得的新信息将极大地促进我们对酒精滥用对艾滋病毒感染患者骨髓生成的负面影响的认识。它还将为开发有效的疗法来治疗艾滋病毒感染的酒精滥用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.