amfAR, The Foundation for AIDS Research

Man (and Woman) Versus Virus

The Evolution of a Possible Treatment

By Jeffrey Laurence, M.D.

February 7, 2008—Most people are familiar with the concept of an evolutionary struggle among different species seeking an advantage in a particular environment, and the ability of species to pass on that advantage genetically. In January, two groups of amfAR-funded researchers expanded that concept to humankind versus virus, generating tantalizing leads for the development of new treatments against HIV.

Host–virus interaction is a classic example of genetic conflict, writes amfAR-funded scientist Dr. Harmit Malik of the Fred Hutchinson Cancer Center in Seattle in the January issue of the journal PLoS Genetics. Both host and virus try to gain advantage over the other in an evolutionary back and forth, usually resulting in rapid changes to proteins of both the virus and the host.

Normal host proteins with the ability to block different stages of viral growth are known as cellular restriction factors. Malik and colleagues mapped the evolutionary success of one such protein—ZAP, or zinc-finger antiviral protein—by tracing its composition and its anti-virus potency from rodents to monkeys to humans.

The further along the evolutionary scale, researchers discovered, the greater the activity of ZAP against certain viruses, including retroviruses. In their laboratory experiments, human ZAP was the most potent of all. Unfortunately, this potency did not extend to efficacy against the retrovirus HIV. But these experiments did validate the success of this experimental technique in identifying potential antiviral factors that exist in normal cells.

In terms of preventing HIV, another cellular restriction protein investigated by amfAR scientists brought more immediate promise. Over the past few years, several amfAR-funded researchers have demonstrated that variants of a normal cell protein, APOBEC3G (found in mammals from mice to monkeys), can prevent the HIV Vif protein from carrying out its evolutionary mandate of facilitating the growth of retroviruses, including HIV. Further up the evolutionary ladder, however, humans harbor a form of APOBEC3G that can be inactivated by Vif. This form of the cell protein fails to prevent Vif from functioning, and thus fails to prevent HIV from growing.

amfAR-funded researcher Dr. Shan Cen of the McGill AIDS Center in Montreal has now discovered the identity of those portions of human APOBEC3G that render it susceptible to HIV Vif-targeted destruction. Moreover, he shows that certain other fragments of APOBEC3G can block this unwanted Vif-APOBEC3G process. Writing in the journal Virology, Cen and his colleagues predict that such fragments may have “potential in anti-HIV-1 therapy” in what is yet another “novel target for anti-HIV-1 drug development” led by amfAR researchers.

Dr. Jeffrey Laurence is amfAR’s senior scientific consultant.