Evaluating the relationship of CD101 and UBE2V1 to genital mucosal inflammation

摘要 全球艾滋病毒1/艾滋病预防工作得到了极大的促进，因为抗逆转录病毒药物 （抗逆转录病毒药物）用于暴露前预防（PrEP）和治疗，因为预防可以有效预防 HIV-1的传播。然而，实现高依从性的挑战、实施成本和潜在的 ARV耐药模式的未来变化强调了对艾滋病毒新方法的持续需求， 1预防。特别是，靶向宿主免疫反应的新干预措施可能不太可能引发病毒感染。 逃逸，并可能增强宿主对未来HIV-1预防疫苗的反应。 已知生殖道炎症与HIV-1感染风险的改变有关。研究 报告说，性传播感染（STI）的炎症反应，生殖道的存在， 炎性细胞因子（例如，IL-7、TNF-α和IL 12 p70），趋化因子（例如，CCL 7和CXCL 9），以及细胞 免疫激活与HIV-1感染风险增加有关。对这些现象的一种解释是 这些炎症环境导致激活的免疫效应细胞的积累， 增加HIV-1感染的现有目标。然而，对肯尼亚女性性工作者的研究发现， 宿主对HIV-1感染的天然抗性与较低水平的免疫激活有关（例如，“免疫 静止”）。这种降低的免疫激活并不反映广泛的免疫抑制状态， 这些妇女对外源性抗原有正常的宿主反应。这表明内在宿主 途径可能调节生殖道炎症反应，这些调节机制可能 改变HIV-1感染的风险。然而，研究也报告说，在某些情况下，免疫激活可能 与减少HIV-1感染有关，这引起了人们的谨慎，即使用干预措施广泛诱导 非特异性免疫抑制可能会产生意想不到的效果，例如消除对HIV-1的有效屏障 或对其他合并感染的防御。公共卫生面临的挑战是识别生殖道 炎症途径，可以减轻HIV-1感染的风险，而不增加其他感染的风险。 感染. 我们最近记录了两个基因CD 101和UBE 2 V1的变异，它们强烈地影响着我们的研究。 与HIV-1感染风险的改变有关。这两个基因以前都被报道在 调节宿主炎症反应。考虑到这些与HIV-1感染风险的遗传关联， 证据表明，这些基因可能会改变宿主的炎症反应，我们假设这些基因可能 通过改变生殖道中潜在的宿主炎症反应来调节HIV-1感染风险。这里 我们建议进行分子和流行病学研究，以评估这些基因变异与 女性生殖道的炎症。

ABSTRACT Global HIV-1/AIDS prevention efforts have been greatly facilitated by the demonstration that anti-retroviral drugs (ARVs) for pre-exposure prophylaxis (PrEP) and treatment as prevention can be effective in preventing the spread of HIV-1. However, the challenges of achieving high adherence, the cost of implementation, and potential for future changes in ARV drug resistance patterns underscore the continuing need for new approaches to HIV- 1 prevention. In particular, novel interventions that target host immune responses may be less likely to elicit viral escape, and may enhance host responses to future HIV-1 prevention vaccines. Genital tract inflammation is known to be associated with altered risk of HIV-1 acquisition. Studies have reported that inflammatory responses to sexually transmitted infections (STI), the presence of genital tract inflammatory cytokines (e.g., IL-7, TNF-α, and IL12p70), chemokines (e.g., CCL7, and CXCL9), and cellular immune activation are associated with increased risk of HIV-1 infection. One explanation for these observations is that these inflammatory environments result in the accumulation of activated immune effector cells, which increase available targets for HIV-1 infection. However, studies of Kenyan female sex workers have found that natural host resistance to HIV-1 infection is associated with lower levels of immune activation (e.g., “immune quiescence”). This reduced immune activation did not reflect a state of broad immunosuppression insofar as these women had otherwise normal host responses to exogenous antigens. This suggests that intrinsic host pathways may regulate genital tract inflammatory responses, and these regulatory mechanisms may alter the risk of HIV-1 infection. However, studies also report that, in some settings, immune activation may be associated with reduced HIV-1 acquisition, raising the caution that use of interventions to broadly induce nonspecific immunosuppression could have unintended effects, such as eliminating effective barriers to HIV-1 or to defenses against other co-infections. The public health challenge is to identify genital tract inflammatory pathway(s) that can mitigate risk of HIV-1 acquisition without increasing risk of other infections. We recently documented the presence of variants in two genes, CD101 and UBE2V1, which are strongly associated with altered HIV-1 infection risk. Both of these genes have been previously reported to have roles in regulating host inflammatory responses. Given these genetic associations with HIV-1 acquisition risk, and a priori evidence that these genes may modify host inflammatory responses, we hypothesize that these genes may modulate HIV-1 acquisition risk through altering underlying host inflammatory responses in the genital tract. Here we propose molecular and epidemiologic studies to evaluate the association of these gene variants with inflammation of the female genital tract.