The global impact of sexually transmitted infections (STIs) is significant. The sexual transmission of viruses such as herpes simplex virus type-2 (HSV-2) and the human immunodeficiency virus type-1 (HIV-1), has been especially difficult to control. To date, no effective vaccines have been developed to prevent the transmission of these STIs. Although antiretroviral drugs have been remarkably successful in treating the symptoms associated with these viral infections, the feasibility of their widespread use for prevention purposes may be more limited. Microbicides might provide an attractive alternative option to reduce their spread. In particular, topically applied small inhibitory RNAs (siRNAs) have been shown to not only block transmission of viral STIs to mucosal tissues both in vitro and in vivo, but also confer durable knockdown of target gene expression, thereby circumventing the need to apply a microbicide around the time of sexual encounter, when compliance is mostly difficult. Despite numerous clinical trials currently testing the efficacy of siRNA-based therapeutics, they have yet to be approved for use in the treatment of viral STIs. While several obstacles to their successful implementation in the clinic still exist, promising preclinical studies suggest that siRNAs are a viable modality for the future prevention and treatment of HSV and HIV. 1. Clinical Context Sexually transmitted infections (STIs) continue to be a major source of global morbidity and mortality [1]. Viral infections, notably herpes simplex virus type-2 (HSV-2) and the human immunodeficiency virus type-1 (HIV-1), have proven particularly problematic to control from both scientific and public health perspectives. HSV-2, the most common cause of genital ulcers, is the most widespread viral sexually transmitted infection (STI) worldwide [2]. Prevalence is high; currently estimated to be ~15–25% of sexually active adults in the US and as high as 60–80% in some developing nations [2–5]. Rates of infection are even higher among women, owing to the greater efficiency of male-to-female (MTF) transmission [6, 7]. While multiple variables factor into the high prevalence rate at the population level, the fact that most sexual transmissions occur in the absence of clinically identifiable genital lesions likely plays a major role [8, 9]. While antiviral drugs have proven effective to reduce viral transmission [6, 8, 10], they are not curative. Furthermore, due to the high costs associated with population-wide screening and maintenance therapy, their utility as public health initiatives
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