SEMEN IN TRANSMISSION OF HIV

描述（由申请人提供）：在HIV-1感染受试者的精液中检测到无细胞和细胞相关的HIV-1。精液中的HIV-1种群已被证明与大多数感染者血液中的HIV-1种群不同。我们最近已经证明，精液中的HIV-1群体在精白细胞和精浆之间进一步亚区隔。此外，这两个精子亚室中的HIV-1可能起源于男性生殖道的不同解剖部位。然而，目前尚不清楚HIV-1是通过精液中无细胞或细胞相关的HIV-1传播，还是通过两者传播。HIV-1在精细胞和精浆之间的区室化提出了这两个精室中的病毒动力学不同的可能性。因此，精液中无细胞HIV-1和细胞相关HIV-1对抗逆转录病毒治疗的反应可能不同。我们的总体假设是，HIV- 1在男性生殖器官中是高度区域化的，这种区域化可以影响传播并对治疗敏感。为了解决这些假设，我们提出了以下具体目标：1)通过分析接受和未接受治疗的男性的精液细胞和精浆中的HIV-1包膜基因，以及接触后感染的女性伴侣的血液中的HIV-1包膜基因，确定精液中的无细胞HIV-1或细胞相关HIV-1是否参与异性传播；2)探讨短期和长期治疗对精液中细胞相关和无细胞HIV-1的影响。在短期治疗期间，通过在治疗前后短时间间隔测量病毒载量来测量精液和血液中无细胞和细胞相关HIV-1的清除率。长期治疗（超过2年）将用于确定抗逆转录病毒治疗是否对精液和血液中无细胞室的病毒库与细胞相关室的病毒库有不同的影响。这将通过测量培养细胞中的病毒表达和HIV-1进化来完成；3)确定HIV-1在男性生殖器官中的解剖位置，评价抗逆转录病毒治疗对男性各种生殖组织中HIV-1的影响。检测hiv -1感染者治疗前后前列腺、精囊、睾丸、输导管和尿道中的病毒RNA水平。我们汇集了所有资源和专门知识，以实现这项建议中所述的具体目标。目的1和2所述研究的精液和血液样本将通过我们正在进行的合作研究从多米尼加共和国和波多黎各的艾滋病毒感染受试者中获得。Aim 3的组织样本将从国家疾病研究交流中心（NDRI）获得。这项研究提供的信息将对我们理解HIV-1治疗后的传播和根除非常有用。

DESCRIPTION (provided by applicant): Cell-free and cell-associated HIV-1 have been detected in semen from HIV-1-infected subjects. HIV-1 populations in semen have been shown to be different than those in blood of most infected subjects. We have recently demonstrated that the HIV-1 population in semen is further subcompartmentalized between seminal leukocytes and seminal plasma. Furthermore, HIV-1 in these two seminal subcompartments may originate from different anatomical sites of the male genital tract. However, there is no information available whether transmission occurs via cell-free or cell-associated HIV-1 or both present in semen. Compartmentalization of HIV-1 between seminal cells and seminal plasma raises the possibility that the viral dynamics in these two seminal compartments are different. Therefore, the responses of cell-free and cell- associated HIV-1 in semen to antiretroviral therapies could be different. Our overall hypothesis is that HIV- 1 in male genital organ is highly compartmentalized and this Compartmentalization can affect transmission and is sensitivity to therapy. To address these hypotheses we propose the following specific aims: 1) To determine whether cell-free or cell-associated HIV-1 in semen is involved in heterosexual transmission by analyzing the HIV-1 envelope gene from seminal cells and seminal plasma from transmitting men with and without therapy, and blood from their infected female partners soon after exposure; 2) To investigate on the effect of short-term and long-term therapy on cell-associated and cell-free HIV-1 in semen. Clearance rate of cell-free and cell-associated HIV-1 in semen and blood will be measured during the short-term therapy by measuring viral load at short intervals before and after therapy. Long term therapy (more than 2 years) will be used to determine whether antiretroviral therapy has a differential effect on the viral reservoir in cell-free compartment as compared to cell-associated compartment in semen and blood. This will be done by measuring viral expression in cultured cells and HIV-1 evolution; 3) To determine the anatomical location of HIV-1 in the male genital organ and evaluate the effect of antiretroviral therapy on HIV- 1 in the various male genital tissues. The level of viral RNA in prostate, seminal vesicle, testes, vas-deference and urethra in HIV-1-infected subjects before and after therapy will be measured. We have assembled all the resources and expertise to accomplish the stated specific aims in this proposal. Semen and blood sample for studies described in Aims 1 and 2 will be obtained from HIV infected subjects from Dominican republic and Puerto Rico though our ongoing collaborative studies. Tissue sample for Aim 3 will be obtained from the National Disease Research Interchange (NDRI).The information from the proposed study will be extremely useful to our understanding of transmission and eradication of HIV-1 following therapy.