Sex Differences in Plasma HIV-1 RNA Concentrations

描述（由申请方提供）：多项研究证明，在CD 4 + T细胞计数大于300个细胞/mm 3时，女性的血浆HIV-1 RNA浓度（VL）显著低于男性。VL性别差异的机制尚不清楚。由于大多数HIV-1复制发生在淋巴组织（LT）中，因此男性和女性LT的差异可能导致VL的差异。我们建议探索两种不同的理论--LT CD 4 + T细胞上CCR 5密度的性别差异和/或每个感染LT细胞产生的病毒体数量的性别差异--来解释女性血浆VL低于男性。本研究的具体目的是：1）确定LT中女性CD 4 + T细胞上的CCR 5密度是否低于男性; 2）确定女性每个有效感染淋巴结细胞的HIV-1 RNA拷贝数是否低于男性。为了实现这一目标，将招募30名未接受抗逆转录病毒治疗且CD 4 + T细胞>300的HIV-1感染女性和35名男性捐献腹股沟淋巴结（LN）和外周血。将使用QuantiBRITE珠系统通过流式细胞术分析来测定解聚的LN CD 4 + T细胞上的CCR 5密度。HIV-1 RNA的RT PCR将用于测定血浆和LN细胞群中的VL。通过HIV-1 RNA的原位杂交测定LN切片中产病毒细胞的频率，并与LN细胞VL结合使用，以计算每个感染细胞的HIV-1 RNA平均拷贝数。在调整CD 4 + T细胞计数、年龄和种族后，将通过线性回归分析数据，以估计性别、VL（血浆和LN细胞中）和LT中CCR 5表达密度或病毒产生细胞频率之间的关系。将比较男性和女性之间在有效感染的LN细胞中HIV-1 RNA的平均拷贝数。二次分析将探索T细胞活化、细胞凋亡和性激素水平与VL、CCR 5密度和每个细胞的平均HIV-1 RNA拷贝数之间的关系。更好地了解VL性别差异的机制可能会导致男性和女性不同的治疗方法，接受激素治疗的HIV-1感染者的不同抗逆转录病毒指南，以及改善HIV-1感染男性和女性治疗的新疗法。

DESCRIPTION (provided by applicant): Multiple studies have documented significantly lower plasma HIV-1 RNA concentrations (VL) in women compared to men at CD4+ T cell counts greater than 300 cells/mm3. Mechanisms underlying sex differences in VL are unknown. Because most HIV-1 replication occurs in lymphoid tissues (LT), it is likely that differences in LT of men and women account for differences in VL. We propose to explore two distinct theories - that sex differences in CCR5 density on LT CD4+ T cells and/or sex differences in numbers of virions produced per infected LT cell exist - to explain lower plasma VL in women compared to men. The specific aims of this study are: 1) To determine whether CCR5 density on CD4+ T cells in LT is lower in women compared to men; and 2) To determine whether the average number of HIV-1 RNA copies per productively infected lymph node cell is lower in women compared to men. To accomplish this, 30 women and 35 men with HIV-1 infection who are not receiving antiretroviral therapy and who have >300 CD4+ T cells will be recruited to donate inguinal lymph nodes (LN) and peripheral blood. CCR5 density on disaggregated LN CD4+ T cells will be determined by flow cytometric analysis using the QuantiBRITE bead system. RT PCR for HIV-1 RNA will be used to determine VL in plasma and LN cell populations. Frequencies of virus-producing cells in LN sections will be determined by in situ hybridization for HIV-1 RNA and used in conjunction with the LN cell VL to calculate the average number of copies of HIV-1 RNA per infected cell. Data will be analyzed by linear regression, after adjusting for CD4+ T cell count, age, and race, to estimate the relationship between sex, VL (in plasma and LN cells), and density of CCR5 expression or frequencies of virus-producing cells in LT. Average number of copies of HIV-1 RNA in productively infected LN cells will be compared between men and women. Secondary analyses will explore relationships between T cell activation, apoptosis, and sex hormone levels and VL, CCR5 density, and average HIV-1 RNA copy number per cell. A better understanding of mechanisms underlying sex differences in VL could lead to different therapeutic approaches in men and women, different antiretroviral guidelines for HIV-1-infected individuals undergoing hormonal therapies, and novel therapies that improve the treatment of both HIV-1 infected men and women.