SEMEN IN TRANSMISSION OF HIV

描述(申请人提供)：在HIV-1感染者的精液中检测到无细胞和与细胞相关的HIV-1。精液中的HIV-1群体已被证明与大多数感染者的血液中的HIV-1群体不同。我们最近证明，精液中的HIV-1群体进一步细分为精液白细胞和精浆。此外，这两个精巢中的HIV-1可能起源于男性生殖道的不同解剖部位。然而，目前还没有信息表明传播是通过无细胞传播还是通过细胞相关的HIV-1传播，还是两者都存在于精液中。HIV-1在精液细胞和精浆之间的区隔增加了这两个精液区段中病毒动力学不同的可能性。因此，精液中无细胞和细胞相关的HIV-1对抗逆转录病毒治疗的反应可能是不同的。我们的总体假设是，HIV-1在男性生殖器中是高度区隔的，这种区隔会影响传播，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)通过分析感染男性的精细胞和精浆以及感染后不久感染的女性伴侣的血液中的HIV-1包膜基因，确定精液中无细胞或细胞相关的HIV-1是否参与了异性传播；2)研究短期和长期治疗对精液中细胞相关和无细胞的HIV-1的影响。在短期治疗期间，将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的HIV-1的清除率。长期治疗(超过2年)将被用来确定抗逆转录病毒治疗是否与精液和血液中的细胞相关室相比，对无细胞室中的病毒储存库有不同的影响。这将通过测量培养细胞中的病毒表达和艾滋病毒-1的进化来完成；3)确定艾滋病毒-1在男性生殖器官中的解剖位置，并评估抗逆转录病毒治疗对男性生殖器组织中艾滋病毒-1的影响。检测HIV-1感染者治疗前后前列腺、精囊、睾丸、输精管和尿路的病毒RNA水平。我们已经汇集了所有资源和专门知识，以实现这项提案中所述的具体目标。目标1和目标2中描述的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者那里获得。AIM 3的组织样本将从国家疾病研究交流中心(NDRI)获得。拟议研究的信息将对我们了解治疗后HIV-1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.