The protein family of helicases separate or unwind duplex nucleic acids such as oligonucleotides, RNA or DNA into single strands. This enzymatic activity is essential for metabolic processes of DNA and RNA replication, transcription etc. and are often associated in enzyme complexes.

To multiply, many pathogens encode their own helicase and/or primase to synthesize DNA. Inhibition of this enzymatic activity abrogates microbial propagation and can lead to the development of potent drugs for treating and curing infection. Recently, helicase-primase inhibitors were reported for the treatment of herpes simplex disease. Almost 25 years after the launch of the milestone antiherpes drug aciclovir (Zovirax®), these drug candidates represent the first compound class which outperforms the only available nucleosidic inhibitors of the herpes TK/DNA-polymerase with respect to all preclinical pharmacological parameters. The helicase-primase enzyme complex appears to be the Achilles heel of herpes simplex viruses and is a prime target of antiinfective drug discovery.All three drugs prevent the herpes simplex virus (HSV) from synthesizing its DNA, but the new compounds target different molecules than acyclovir. They inhibit a complex of three proteins, called the helicase-primase enzyme complex, which plays a key role in DNA synthesis. Acyclovir (whose trade name is Zovirax) blocks the polymerase enzyme.

"In animal models of HSV infection, the new drugs appear to have therapeutic value rivaling or exceeding that of acyclovir," write Clyde S. Crumpacker and Priscilla A. Schaffer of Harvard Medical School in Boston, Massachusetts in a News and Views piece accompanying the two papers in Nature Medicine. "Carefully controlled clinical trials in humans are clearly the next step for both classes of compounds."

In the first drug study, Gerald Kleymann and colleagues at Bayer AG in Wuppertal, Germany, found that a compound called BAY 57-1293 accelerates the healing of herpes lesions in mice and reduces the severity and frequency of recurrent disease.

In a similar study, James Crute, of Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut, and colleagues found that another compound called BILS 179 BS is highly effective against skin and vaginal herpes lesions in a mouse model of the disease.

Herpes simplex virus types 1 and 2 are responsible for the cold sores and genital herpes that have plagued humanity for centuries. Despite the availability of acyclovir therapy, the herpes simplex virus can cause life-threatening infections such as herpes encephalitis. Neither acyclovir nor the new drugs can eliminate the virus in the latent state. 

If ongoing clinical trials pan out, it's possible that one day people could be cutting their risk of HIV infection simply by popping a couple of pills per day. The pills are cheap, safe, and have been on the market for years. The catch? These drugs don't target HIV, they fight off herpes.

Simply quelling genital herpes could be enough to substantially reduce an individual's risk of acquiring and transmitting HIV. Researchers have long known that sexually transmitted infections (STIs) play a facilitative role in HIV transmission. Now nearly a dozen clinical trials are investigating whether drugs that suppress herpes simplex virus-2 (HSV-2), the causative agent of genital herpes, can reduce HIV transmission.

Preventive approaches that aim to modify behavior are yielding only modest gains against HIV transmission, so many researchers are now exploring such innovative biological preventive measures—earlier this year a clinical trial in South Africa found that male circumcision could reduce the risk of HIV acquisition.

Prevention strategies that focus on biology rather than behavior, or a combination of the two, may provide greater gains in prevention than a behavioral approach alone. "Aside from individual behavior change, we don't really have ways to prevent HIV transmission," says Anna Wald, an epidemiologist at the University of Washington School of Public Health and Community Medicine, Seattle. "That is the starting point of why we are looking at herpes."

But before researchers can go distributing drugs against herpes to HIV at-risk populations they need to demonstrate that these medications can reduce HIV transmission in real world settings, says Jairam Lingappa, medical director of one of the studies organized by the University of Washington. "While epidemiologic studies show a relationship between HIV and genital herpes," he says, "we don't yet have a clear demonstration of the public health benefit of using HSV-2 suppression."

Herpes is a lifelong infection and the virus cycles between latency and reactivation to cause clinical disease, producing painful ulcers at the genital mucosa. Numerous studies have found a strong association between genital ulcer diseases and increased HIV transmission (Herpes 11 Suppl. 1, 36A, 2004). HIV is rather inefficient at spreading via sexual intercourse, leaping from one person to another in perhaps as few as one time out of every 1000 sexual exposures under certain conditions. Genital sores facilitate transmission by disrupting the physical barrier of the skin and enabling HIV to much more easily enter the body. In addition, genital herpes causes inflammation that recruits dendritic cells (DCs) and activated CD4+ T cells to the genital mucosa. There, DCs can entrap HIV particles and then traffic them to CD4+ T cells at distant sites like the lymph nodes.

So controlling these ulcers should reduce HIV transmission. Yet two large trials in the early 1990s, one conducted in Mwanzaa, Tanzania and the other in Rakai, Uganda, yielded conflicting results. The trials involved treating curable STIs such as syphilis, gonorrhea, chlamydia, and trichomoniasis, but not genital herpes, a strategy that resulted in a 40% reduction in HIV-transmission rate in Tanzania but no reduction in Uganda. The differing results are thought to be due to population characteristics, notably that the Tanzania cohort exhibited more high-risk behavior than the cohort in Uganda, where the HIV epidemic was more mature. (J. Infect Dis. 191 Suppl. 1, S168, 2005). However, some researchers believe that another factor was the lack of herpes treatment, which is not curable and is the most widespread STI in sub-Saharan Africa. In some regions of Africa, HSV-2 seroprevalence is greater than 80% in men and women 35 and older. (J. Infect. Dis. 186 Suppl. 1, S3, 2002).

Vicious cycle

Individuals with genital herpes are at 3 times greater risk of acquiring HIV, according to a just published meta-analysis of 19 studies (AIDS 20, 73, 2006) conducted by Esther Freeman and colleagues at the London School of Hygiene and Tropical Medicine (LSHTM). The increase in risk was roughly the same in both men and women in the general population.

What is more, the proportion of HIV transmission events due to HSV-2 could be on the rise, according to a presentation from Freeman at the July 2005 International Society for Sexually Transmitted Disease Research meeting in Amsterdam. "The population-attributable fraction of new HIV infections due to HSV-2 is increasing over time in African populations," she said.

This elevated risk of acquiring HIV may be greatest in the first few months following infection with HSV-2, when severe outbreaks are most common (J. Infect. Dis. 187, 1513, 2003). "The severity of these first episodes appears to account for the ability of HIV to infect the individual," says Steven Reynolds, an infectious disease specialist now at the US National Institutes of Health working in Uganda.

Genital herpes heightens the risk not only of acquiring HIV but also of transmitting it to a sexual partner. HSV-2 replication, even if actual herpes sores are not present, can lead to more frequent and greater amounts of HIV shedding in the genital tract since HSV-2 regulatory proteins can interact with a regulatory region of the HIV genome to upregulate its replication. And acute episodes of genital herpes result in transient increases of HIV RNA levels in the plasma (J. Acquir. Immune Defic. Syndr. 35, 435, 2004).

In addition, HSV-2 is one of the most common opportunistic infections and takes advantage of the immunocompromised status of HIV-infected persons to cause frequent and prolonged outbreaks of genital herpes. So the vicious cycle is complete: HIV-related immunosuppression causes more HSV-2 to be present in the genital tract, which in turn promotes more HIV replication.

These lines of evidence open up the exciting possibility that suppressing HSV-2 could reduce both the risk of acquiring HIV (acquisition) and the risk of transmitting it to a sexual partner (infectiousness).

Herpes suppression on trial

To examine the public health benefit, a number of clinical trials are starting up to assess whether giving a drug to suppress HSV-2 can knock down HIV transmission . These randomized, blinded, placebo-controlled trials will evaluate treatment with acyclovir, a proven anti-herpes drug efficient at suppressing HSV-2 activity, particularly clinical episodes.

Acyclovir is affordable, it has few side effects, and the virus rarely becomes resistant, even after years. The drug is typically used in two ways: as a long-term suppressive therapy and as an episodic treatment when herpes flares up. The suppressive regimen helps keep HSV-2 latent, reducing the frequency and severity of outbreaks. The episodic treatment shortens the duration of the outbreak, although only by about one day out of a six-day period. Often by the time people seek treatment the outbreak has been going on for several days. Because of this relatively small improvement, acyclovir is not a standard treatment for genital herpes under World Health Organization guidelines.

Yet some researchers, including Philippe Mayaud of the LSHTM, think episodic treatment could significantly reduce the amount of HIV shed. He is involved in three studies, one of which is looking at HIV transmission when acyclovir is given to women in Ghana and the Central African Republic who come to clinics seeking treatment for genital herpes. Women who consent to be in the study are HIV tested and offered acyclovir three times a day for five days or a placebo. Mayaud and his colleagues will take genital samples from all women to see if they shed less HSV-2 and HIV (the latter among HIV-infected women only) due to the acyclovir treatment; the HIV-uninfected women will be followed to see if acyclovir protects them from acquiring HIV. "If you control the HSV-2 shedding it may have longer lasting effect on HIV shedding than just the duration of the episodic treatment per se," says Mayaud.

Episodic versus suppressive therapy

Episodic treatment alone may not be enough, however. It does not control asymptomatic HSV-2 shedding, a situation that researchers now know is extremely common. "If you looked only at the symptomatic phase, you'd miss a lot of the shedding," says Lingappa. So Mayaud and other research teams are exploring suppressive therapy.

One such study is testing this concept in female bar- and hotel-workers in Tanzania. A suppressive regimen of acyclovir or a placebo is being given to 1000 HIV-infected and HIV-uninfected women in a trial led by Debby Watson-Jones at the LSHTM. The HIV-uninfected women are being monitored for seroconversion, while the HIV-infected women are being monitored to see if the suppressive acyclovir regimen decreases their HSV-2 shedding and consequently their HIV shedding. Together with colleagues from Burkina Faso and the University of Montpellier in France, Mayaud is also exploring how highly active antiretroviral therapy (HAART) may alter HSV-2's impact on HIV shedding. "All these shedding studies will be very important benchmarks for the effect of different interventions for HSV-2 or HIV," he says.

While shedding studies are important, what researchers really want to know is whether acyclovir can reduce HIV acquisition in people who have HSV-2. A large scale study to answer that question is being conducted by Wald and Connie Celum, also of the University of Washington. The study is following women in three African nations (South Africa, Zambia and Zimbabwe) and men who have sex with men (MSM) in the US and Peru to see if acyclovir gives them protection against acquiring HIV. The researchers will also be looking at how well the drug controls the occurrence and frequency of genital ulcers, whether the participants adhered to the regimen of two pills daily, and also the effect of acyclovir on HIV setpoint in HIV seroconverters. "The trial of 3200 women and men is over 80% enrolled with excellent retention and adherence, so we are optimistic that we will get an answer about the degree to which genital herpes increases HIV susceptibility," says Celum.

The buck stops here

Another important question is whether acyclovir can prevent HIV-infected individuals from passing the virus to a partner. The best way to answer this question is with a study of so-called "HIV discordant" couples, where one partner is infected with both HIV and HSV-2 and the other partner is not infected with HIV. Such a study is now starting up led by Celum, Wald, and Lingappa. The study will track nearly 3000 HIV discordant couples at twelve sites in seven African countries. The HIV-infected, HSV-2-infected partner will be given either acyclovir or a placebo to see if they are at reduced risk of passing HIV to their non-infected partner, in the context of couples' counseling, bacterial STI treatment, and condom provision.

If acyclovir proves capable of reducing HIV transmission the trial results will benefit everyone—but none so much as the discordant couples themselves. HSV-2 is the biggest cause of genital ulcers in married couples, says Susan Allen, a professor at Emory University's Rollins School of Public Health and a pioneer in studying HIV-discordant couples. "When there is an HIV transmission event," says Allen, "85% of the time the virus is acquired from the spouse."

An exciting aspect of the study of herpes suppression among HIV-discordant couples is the implementation of strategies to promote couples' counseling and recruitment of HIV-discordant couples in Africa, says Celum. A counseling program developed collaboratively by Allen, Liverpool Voluntary Counseling and Testing, and staff at the US Centers for Disease Control and Prevention has been used at some study sites to help couples understand the risks they face and help them make choices about how to minimize that risk. "This time period [when one partner is infected and the other is not] is a critical window in which to implement a public health strategy to reduce transmission," says Lingappa. "If we can enhance the number of families that maintain one healthy parent or adult, that is one of the things we should promote."

While well designed, no study can answer every question. The couples study is meant to examine acyclovir's role in preventing HIV transmission to the HIV-uninfected partner, but it does not test whether a greater reduction in intra-couple transmission could result if both members of the couple took acyclovir, to prevent both the infected partner from transmitting HIV and the uninfected partner from acquiring it. By studying acquisition and infectiousness in two separate trials, the researchers run the risk of finding only weak associations in both. But Celum says the team carefully considered combining the trials and decided it would be better to separate the studies to determine the relative impact of acyclovir on acquisition and infectiousness.

A medicine for the masses?

If the trials are successful, what will that mean for the average person who is at risk of either acquiring the disease or, if they have it already, transmitting it to a partner? Mayaud hopes that if the episodic treatment proves successful acyclovir will be offered as a standard treatment for genital herpes when people visit a clinic.

Suppressive therapy—that is, a 400 mg pill of acyclovir twice a day for years—will be expensive and difficult to distribute in Africa. Valacyclovir, the newer form that can be taken just once a day, is not yet produced generically. A year's course of generic suppression therapy could cost as little as US$40 per year in Africa, but that is still prohibitive in most settings. Despite the costs, most researchers argue that if there is a remedy on the shelf that can be used to reduce HIV transmission it should be made available. "Until the day comes when an effective AIDS vaccine is developed," says Pat Fast, medical director at the International AIDS Vaccine Initiative, "researchers must try everything they can to stem the spread of HIV."

"If you ask me can you deal with a global epidemic by just giving someone a pill, my answer is no," says Wald, who adds that she hopes the trials will add impetus to developing an HSV-2 vaccine. "However, I feel strongly that if the results of this trial are positive, it will clearly be very important on an individual basis to use this for prevention of HIV acquisition or transmission."