Aciclovir, herpes viruses and HIV: a never-ending story.

The present manuscript reviews the study of Delany et al. on the impact of herpes simplex virus type 2 (HSV-2) suppressive aciclovir on genital and plasma HIV-RNA in 269 HSV-2/ HIV-coinfected women in South Africa [1]. HIV infection continues to be among the leading causes of global morbidity and mortality, especially in Africa. An estimated 40 million people are HIV positive with an annual mortality of 3 million. The rapid spread of HIV as a sexually transmitted infection (STI) is exceeded by that of HSV-2 [2–4]. The chronic nature of HSV-2 infection with frequent and mostly unrecognized reactivations [5,6], and its relatively large transmission probability per coital act [7,8], leads to HSV-2 having a different epidemiology from STIs. Indeed, the prevalence of HSV-2 has already reached high seroprevalence, of up to 90% in HIV-positive patients, and HSV-2 is now the leading cause of genital ulcer disease (GUD) in both developing and developed countries [2,4,9,10]. The epidemiological data indicate that HIV and HSV-2 have overlapping prevalence patterns around the globe [11–15]. The epidemiological overlap between the two viruses, as well as the nature of HSV-2 infection as a leading cause of clinical and subclinical genital ulceration and mucosal disruption, have suggested a role for HSV-2 in the elevation of the HIV pandemic since the late 1980s [16]. Two systematic reviews of 18 longitudinal studies showed that HSV-2 seropositivity has a relative risk of 2 or higher for HIV acquisition, after controlling for sexual behavior [17,18]. These epidemiologic observations have been corroborated by evidence of biological plausibility. CD4 lymphocytes, HIV target cells, have been detected in herpetic lesions [19,20], which could increase HIV susceptibility during sexual exposure, and evidence was obtained that the same cells can produce in vitro HIV pseudotyped by the HSV-1 envelope [21]. Furthermore, the evidence that HSV-2 increases HIV transcription in vitro [22–26] potentially explains the high levels of HIV RNA seen in herpetic lesions [27] and in plasma in dually infected patients [28–30], and supports higher HIV infectivity in dually infected individuals [31]. This has been corroborated by epidemiologic studies that suggested a Antonio Volpi†, Cesare Sarrecchia and Pasquale Sordillo Author for correspondence Department of Public Health, University of Rome Tor Vergata, Via Montpellier 1, 00133 Roma, Italy Tel.: +39 062 090 3440 Fax: +39 062 090 3441 [email protected] Evaluation of: Delany S, Mlaba N, Clayton T et al. Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 23, 461–469 (2009).