Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Curr Opin Infect Dis. 2009 Dec;22(6):583-7. doi: 10.1097/QCO.0b013e32833229b8.
Epidemiological studies have demonstrated that HIV-1 and herpes simplex virus-2 (HSV-2) are responsible for two epidemics and that, by overlapping in risk populations, they reinforce the spreading of both HIV-1 disease and genital herpes. Randomized controlled trials have investigated whether acyclovir (ACV), a synthetic drug designed to suppress herpes viruses, might provide an inexpensive and safe way to drastically reduce HIV-1 spreading around the world. The controversial results of these trials are reviewed below in light of the recent discovery of the direct suppression of HIV-1 by ACV.
Recent studies have shown that although ACV therapy does not prevent HIV-1 transmission, it decreases plasma, genital, rectal, and seminal HIV-1 RNA levels. The decrease of HIV-1 load has been believed to be the result of an indirect mechanism and explained by reduction of HSV-2-mediated inflammation. The discovery of the direct inhibitory activity of ACV on HIV-1 reverse transcriptase brings new insights into the interpretation of these results. Also, it is important to understand why HSV-2-suppressive therapy with ACV did not reduce HIV-1 acquisition/transmission.
The direct suppression of HIV-1 by ACV activated by coinfecting HSV-2 may in part explain the ACV-induced decrease of HIV load reported in several clinical trials. If this is the case, other herpes viruses capable of ACV activation may contribute to this effect. New basic studies and new targeted clinical trials are needed to understand whether ACV therapy can also be beneficial for HSV-2-negative patients. These studies will show whether ACV therapy should be included in HIV-1 treatment as well as whether ACV-based drugs specifically targeting HIV-1 can be developed.
流行病学研究表明，HIV-1 和单纯疱疹病毒-2（HSV-2）导致了两种流行病，由于它们在高危人群中重叠，这两种病毒的传播都加剧了 HIV-1 疾病和生殖器疱疹的传播。随机对照试验已经研究了阿昔洛韦（ACV）——一种旨在抑制疱疹病毒的合成药物——是否可以提供一种廉价且安全的方法来大大减少全球范围内 HIV-1 的传播。鉴于最近发现 ACV 可直接抑制 HIV-1，下面将综述这些试验的有争议结果。
最近的研究表明，尽管 ACV 治疗不能预防 HIV-1 传播，但它确实降低了血浆、生殖器、直肠和精液中的 HIV-1 RNA 水平。HIV-1 载量的减少被认为是间接机制的结果，并通过减少 HSV-2 介导的炎症来解释。ACV 对 HIV-1 逆转录酶的直接抑制活性的发现为解释这些结果提供了新的见解。此外，了解为什么 HSV-2 抑制性治疗用 ACV 不能减少 HIV-1 的获得/传播也很重要。
被 HSV-2 共感染激活的 ACV 对 HIV-1 的直接抑制作用可能部分解释了几项临床试验报告的 ACV 诱导的 HIV 载量下降。如果是这样，其他能够被 ACV 激活的疱疹病毒也可能对此有贡献。需要新的基础研究和新的靶向临床试验来了解 ACV 治疗是否也对 HSV-2 阴性患者有益。这些研究将表明 ACV 治疗是否应包含在 HIV-1 治疗中，以及是否可以开发专门针对 HIV-1 的 ACV 类药物。
