Chronic viral infections cause enormous suffering among infected individuals, highlighting the need for curative therapies. Thirty-three million people worldwide are infected with human immunodeficiency virus type 1 (HIV-1), and the annual global incidence is approximately 2.6 million infections (186
). With the advent of highly active antiretroviral therapy (HAART), HIV is now managed as a chronic rather than a terminal disease (108
) and treated patients have a normal life span (6
). However, only 36% of those in need of antiretroviral regimens in low- and middle-income countries have access to therapy (186
). Without treatment, the median time for progression to AIDS is 9 to 10 years and the average life expectancy upon developing AIDS is 9 months (113
). Moreover, HAART does not cure the infected individual or reverse all disease manifestations, and therapy is lifelong. Other sobering facts include possible development of drug resistance and long-term adverse effects of current drugs, as well as the enormous financial burden of lifelong treatment in populations in which HIV is endemic (120
Hepatitis B virus (HBV) is another infection of enormous public health importance. Though an effective vaccine is available, global uptake is low (51
). Over 350 million people are chronically HBV carriers, and more than 50% of people within certain regions of Asia and Africa have a history of HBV exposure. Cirrhosis, liver failure, and hepatocellular carcinoma (HCC) related to HBV claim 500,000 to 1.2 million lives annually (36
). Antiviral therapy is effective for preventing these outcomes but does not eliminate all reservoirs of virus. Only a small fraction of the infected population has access to therapy, which typically must be given over years (209
). Liver transplantation, an option for infected persons with end-stage disease, is unavailable for the majority of those in need.
Herpes simplex virus (HSV) is also a cause of significant morbidity. HSV-2 is the leading cause of genital ulcers worldwide, and 16% of Americans are seropositive (208
). HSV-1 prevalence exceeds 50% in the United States: this serotype can cause both oral and genital ulceration and is the most common etiology of infectious blindness (keratitis) and viral encephalitis (158
). Both varieties of HSV cause severe infections in newborns and immunocompromised hosts (17
). Importantly, HSV-2 is a key risk factor for HIV-1 acquisition and transmission (163
). While antiviral therapy decreases the severity of primary infection and recurrent ulcer formation and also decreases the frequency of asymptomatic viral shedding and recurrences, it is imperfect for each of these indications (38
). Several candidate vaccines failed to demonstrate efficacy (37
Effective antiviral therapies exist for treatment of each of these infections, and development of these agents represents one of the major successes in medicine during the previous decades. Accordingly, the search for new antiviral medications continues to be a major focus within virology. Unfortunately, antiviral therapies may have limited room for improvement. While existing treatments for HIV, HBV, and HSV inhibit replication and cellular entry of the virus extremely potently (164
), they do not target latent viral stores which exist in a reversible nonreplicating state of infection. HIV-1, HBV, and HSV establish long-lived reservoirs from which newly synthesized viruses can continually arise. When antiviral agents are stopped, robust viral replication often resumes, and symptomatic manifestations of disease typically follow.
Because antiviral therapy is safe and mostly effective for these infections, relatively little attention has been paid to approaches that might rid the body of latent virus. However, a deeper understanding of the molecular nature of latent viral genomes and their cellular and anatomic sites has raised the possibility that new therapies may directly attack the Achilles' heel of chronic viral infections. Recently, new technologies that may allow specific disruption of latent viral genomes have been developed. In this review, we outline why highly specific, DNA-cleaving enzymes, an exciting technology that was recently recognized as the “Method of the Year” (110
), may enhance the likelihood of a cure. We review the major classes of such enzymes and consider specific issues for their use in addressing the unique latent reservoirs for HIV-1, hepatitis B, and HSV-2.