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VACCINE RESEARCH Herpesvirus Used to Spur Defense Against HIVTwo Harvard researchers have collaborated on developing an HIV vaccine using a novel vector—the herpesvirus. David Knipe, the Higgins professor of microbiology and molecular genetics and a specialist in herpes simplex virus, has joined with HIV vaccine researcher Ronald Desrosiers, professor of microbiology and molecular genetics and director of the New England Regional Primate Research Center, to capitalize on the longevity of herpes to create a vaccine that theoretically would achieve long-lived immune responses against HIV. They have used a live attenuated herpes vaccine to express SIV proteins, yielding some encouraging results in nonhuman primates, published in the September Journal of Virology. Herpes gets its name from the Greek word herpein, "to creep," and as its etymology suggests, it has a habit of creeping into the sensory neurons innervating its site of infection—usually the epithelial cells lining the mouth or genital tract. In the nervous system, the virus is able to evade immune responses and lie latent for the lifetime of its host. Knipe and Desrosiers thought that the virus's ability to elicit persisting immune responses might make it a worthy adversary to combat another aggressive virus, HIV. HIV has a staggering ability to thwart the immune system early in an infection and then replicate unrelentingly. "For a vaccine to overcome that is asking a lot of a vaccine," said Desrosiers. The double-edged sword of vaccine development is that battling a powerful virus requires a powerful opponent, but when the vaccine is too good at provoking an immune response, it can cause disease itself. Olympic TrialsThe search for an HIV vaccine has recently received a boost of federal funding to help add to the nearly 30 potential vaccines that have been brought to clinical trials. But researchers face several hurdles. HIV can only be approximated in animal models, using versions of SIV in monkeys as an analogy. Different stocks of SIV vary in how virulent they are, and no one really knows where HIV fits into this continuum; consequently, results from animal tests can vary according to which strain was used to challenge the animals. It is also difficult to evaluate the quality of immune responses to HIV vaccines because of the breadth of immunity necessary to protect against HIV.
David Knipe's team (top) worked with Ron Desrosiers's (bottom) to join research on herpes and HIV. Pictured above are (l to r) David Knipe, William Lucas, and Cynthia Murphy. Below are (l to r) Paul Johnson, Amitinder Kaur, Susan Czajak, and Robert Means. Top photo by Steve Gilbert
Most vaccines being studied now focus on three main delivery systems: HIV protein subunits, a naked DNA plasmid encoding HIV proteins, or a live vector vaccine that carries selected HIV genes, using vectors such as the vaccinia virus, canarypox virus, or salmonella. Each approach has advantages and disadvantages: the vaccines that do not contain a live virus have no chance of causing disease, but they may not be as effective as a live vector at inciting the immune system. Because HIV has many strategies to attack its host, no vaccine so far seems to be able to counterattack on all fronts. Knipe and Desrosiers hoped that a herpes vector would provide a key difference that other vectors lack: like a bad guest, it simply refuses to leave. One of the drawbacks of otherwise promising vaccines so far is that despite inciting an impressive immune response, they are not able to maintain immunity over prolonged periods of time. Although this may not matter in animals that are exposed to the virus two weeks after getting a vaccine, it would certainly be unrealistic for humans. "Herpes was a potentially attractive vector because of the longevity of the immune response," said Knipe. But Desrosiers initially expected that a herpes vector would need to replicate in its host in order to achieve a persistent immunity, although an ability to replicate would cause safety concerns even if the virus were attenuated. To see if viral replication was needed to generate lasting immunity, Knipe's research fellows Cindy Murphy and Bill Lucas engineered two vaccines, one that could replicate and one that could not. Surprisingly the two vaccines seem to perform equally well, and both generate stable immune responses. "We have a paradox there that we haven't explained yet, why we have durable immunity even though the virus isn't going latent," said Knipe. The Bright SideIn the team's initial study of the vaccine in nonhuman primates, two of seven of the animals were completely protected from the virus, and one was able to clear the virus almost completely. Three of seven may not sound like very good odds, but Desrosiers said they are encouraging for several reasons. The animals were challenged with SIVmac239, a particularly virulent strain, about five months after receiving the final dose of the vaccine, a much longer period of time than other studies use. And in the field of HIV vaccines, few tactics achieve even these results. Finally, there are many ways to optimize the method to get better results. The initial vaccine encoded only for SIV envelope proteins, but the next generation of the vaccine will include an additional protein thought to be a target for the killer T cells that seem to be especially important for immunity to HIV.Still, the idea of using a herpesvirus as a vaccine raises serious safety concerns that the team must address, although there is a precedent for it in the live attenuated chickenpox vaccine Varivax, which is also a herpesvirus. Knipe has worked on creating a safe candidate vaccine for HSV-2, the virus responsible for genital herpes, that is also detailed in the September Journal of Virology. This vaccine is a replication-defective mutant virus with two engineered mutations in genes needed for viral DNA synthesis. If Knipe's HSV-2 vaccine proves safe and effective, it could also be used as a vector for an HIV vaccine. Knipe and Desrosiers have begun studies of an SIV vaccine using an HSV-2 vector rather than the HSV-1 vector they initially used, because HSV-2 seems to infect the monkey's cells more easily. Ideally, the HSV-2 vector could serve a double role as a vaccine for HIV as well as genital herpes. "There are all kinds of reasons to be optimistic," said Desrosiers. "I'm generally a pessimist in these matters, and I'm really pretty excited about this." —Courtney Humphries
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