Cong Mian-Er, Pau Chou-Pong, Heneine Walid, García-Lerma J Gerardo
Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
PLoS One. 2016 Nov 2;11(11):e0164821. doi: 10.1371/journal.pone.0164821. eCollection 2016.
Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) is a novel HIV prevention strategy. Suboptimal PrEP adherence and HIV infection creates an opportunity for continued antiretroviral drug activity during undiagnosed infection. We previously showed that macaques infected with SHIV during PrEP with FTC/TDF display reduced acute plasma viremias and limited virus diversity. We investigated the effect of PrEP on acute SHIV DNA dynamics and on the size of the persistent virus reservoir in lymphoid tissues.
Cell-associated SHIV DNA levels in PBMCs were measured in 8 macaques infected during PrEP with FTC/TDF or single-agent TAF and was compared to those seen in untreated infections (n = 10). PrEP breakthrough infections continued treatment with 1-2 weekly drug doses to model suboptimal drug exposure during undiagnosed HIV infection in humans. SHIV DNA was also measured in lymphoid tissues collected from FTC/TDF PrEP breakthroughs after 1 year of infection.
Compared to untreated controls, PrEP infections had reduced plasma RNA viremias both at peak and throughout weeks 1-12 (p<0.005). SHIV DNA levels were also reduced at peak and during the first 12 weeks of infection (p<0.043) but not throughout weeks 12-20. At 1 year, SHIV DNA reservoirs in lymphoid tissues were similar in size among macaques that received PrEP or placebo.
Antiviral drug activity due to PrEP limits acute SHIV replication but has only a transient effect on cell-associated SHIV DNA levels. Our model suggests that suboptimal drug exposure in persons that are taking PrEP and become infected with HIV may not be sufficient to reduce the pool of HIV-infected cells, and that treatment intensification may be needed to sustain potential virological benefits from the PrEP regimen.
恩曲他滨和替诺福韦酯（FTC/TDF）暴露前预防（PrEP）是一种新型的HIV预防策略。PrEP依从性欠佳以及HIV感染为未诊断感染期间持续的抗逆转录病毒药物活性创造了机会。我们之前表明，在使用FTC/TDF进行PrEP期间感染SHIV的猕猴表现出急性血浆病毒血症降低且病毒多样性有限。我们研究了PrEP对急性SHIV DNA动态以及淋巴组织中持续病毒库大小的影响。
在8只在使用FTC/TDF或单药替诺福韦艾拉酚胺（TAF）进行PrEP期间感染的猕猴中测量外周血单核细胞（PBMC）中细胞相关的SHIV DNA水平，并与未治疗感染的猕猴（n = 10）进行比较。PrEP突破性感染继续以每周1 - 2剂药物进行治疗，以模拟人类未诊断HIV感染期间欠佳的药物暴露情况。在感染1年后，还对从FTC/TDF PrEP突破性感染猕猴收集的淋巴组织中的SHIV DNA进行了测量。
与未治疗的对照组相比，PrEP感染在峰值以及整个第1 - 12周的血浆RNA病毒血症均降低（p<0.005）。SHIV DNA水平在感染峰值以及前12周也降低（p<0.043），但在第12 - 20周期间未降低。在1年时，接受PrEP或安慰剂的猕猴中，淋巴组织中的SHIV DNA库大小相似。
PrEP引起的抗病毒药物活性限制了急性SHIV复制，但对细胞相关的SHIV DNA水平仅具有短暂影响。我们的模型表明，正在接受PrEP并感染HIV的人欠佳的药物暴露可能不足以减少HIV感染细胞库，可能需要强化治疗以维持PrEP方案潜在的病毒学益处。
