Tweaking the Genes

One of the most compelling areas of HIV treatment research combines the newest cutting-edge science with ancient immune-system defenses that are millions of years old. Called RNA interference, this approach to HIV suppression works by sabotaging the genetic coding for the production of key HIV genes or manipulating genetic processes in immune-system cells to either create anti-HIV activity or shut down cellular processes that the virus hijacks to copy itself. The genetic discovery has such enormous potential for viral disease treatment that Science named it the breakthrough technology of 2002 and Technology Review dubbed it one of the top 10 emerging technologies for 2004. One particularly intriguing area of RNAi research was enabled by the recent discovery of an ancient human enzyme'APOBEC3G'that thwarts the reproduction of viruses inside infected cells. Unfortunately, a corresponding gene in HIV'viral infectivity factor, or Vif'neutralizes APOBEC in the body, which cripples the natural defense. Therapies that turn off the Vif gene or that keep APOBEC permanently turned on could prevent viral replication in infected cells. Another protein discovery also could be a useful target for gene therapy, according to researchers from Boston's Dana-Farber Cancer Institute and Harvard University. Rhesus monkeys were shown to possess an antiviral protein called TRIM5-alpha, which prevents HIV from fully shedding its outer coat, a process that must occur before the virus can replicate. Humans have a similar but weaker version of the naturally occurring protein, the researchers report. Preclinical studies backed by the National Institute of Allergy and Infectious Diseases are under way to manipulate the human protein in an effort to boost its antiviral effects. Researchers at Duarte, Calif.'s City of Hope also are studying RNAi's ability to interfere with another key HIV gene'rev, according to John Rossi, MD, chair of the Beckman Research Institute's Division of Molecular Biology within City of Hope. Other scientists are attempting to use RNAi to cripple the virus's nef, gag, tat, or env genes by creating faulty genetic codes for their creation, or to 'turn on' or 'turn off' key human genes as well. Although the therapeutic potential of RNAi treatments is perhaps unmatched in HIV research, many leading treatment advocates note that the field is still in its infancy. But Warner Greene, MD, Ph.D., director of the Gladstone Institute for Virology and Immunology, is more enthusiastic. 'From what we've seen so far, this can stop the virus stone-dead,' he says. 'I really think what we'll be seeing in about three to five years are new drugs that work on APOBEC3G or Vif. It's going to be a very exciting time.'