amfAR Grantee Uncovers Critical Weakness in HIV
August 13, 2003—Why does HIV infect humans but not other species? amfAR grantee Dr. Roberto Mariani and his mentor Dr. Ned Landau of the Salk Institute in La Jolla, CA, have filled in one more piece of the puzzle. Their findings, published in the July 11 issue of the journal Cell and presented at the Second International AIDS Society Conference held in Paris July 13-16, might prove useful for scientists developing new drugs to combat HIV—and could even be used to devise a cure for the virus.
Dana Gabuzda, M.D.
Dr. Mariani and others in the same lab are working to understand the ongoing struggle between the virus and the natural defenses in our bodies that try to prevent infection from taking place. In particular, Dr. Mariani is focusing his attention on a small protein called Vif that is produced by HIV. Human cells fight a losing battle against HIV in part because Vif, or viral infectivity factor, allows HIV to overcome a cell’s natural anti-HIV defenses. When Vif is not present, HIV infection occurs but the offspring viruses are not able to infect other cells in the body, and the process of infection comes to a halt.
Until now, scientists had a hazy understanding of why this happens. Building on recent findings reported by others in the field, Dr. Mariani and colleagues closely studied the interaction between Vif and a protein found in many cells called APOBEC3G. APOBEC3G appears to play a protective role in the cells of humans and other species. When Vif is not present, APOBEC3G attaches to the virus inside the cell and degrades its genetic material, rendering the virus unstable and incompetent to productively infect other cells. When Vif is present, however, it locks onto APOBEC3G and prevents the cell protein from degrading the genetic material of the virus.
Interestingly, the version of the APOBEC3G protein found in other species varies slightly from that of its human counterpart. In those other species, the HIV protein Vif is unable to lock onto APOBEC3G. Therefore, APOBEC3G is incorporated into the offspring virus and degrades it.
“We’re very excited that these new findings may pave the way for a number of different anti-HIV drug therapeutics,” says Dr. Mariani. “Drug companies might be able to develop compounds that would prevent the interaction between Vif and APOBEC3G. Without this interaction, the HIV infection process would be halted.”
Meanwhile, another amfAR grantee, Dr. Dana Gabuzda of the Dana Farber Cancer Institute in Boston, is working to identify small molecules that could inhibit Vif. As part of a new, super-targeted research initiative funded by amfAR in 2001, Dr. Gabuzda was charged with developing new technology to search for compounds that inhibit the viral protein.
“I’m excited to be involved in one of the first serious attempts to study Vif as a potential therapeutic target,” said Dr. Gabuzda. “Until now, research on Vif as a target for anti-HIV drugs has been greatly limited by our relatively poor understanding of its structure and its function. However, given new technology and the current state of knowledge, I think it’s time to begin directing a more significant effort towards developing Vif as a potential therapeutic target.”