Host Resistance Factors Preventing HIV Infection
By Jeffrey Laurence, M.D.
November 20, 2006—The October issues of two prestigious scientific journals, Science and Proceedings of the National Academy of Sciences, feature articles co-authored by three amfAR-funded investigators. They address a single critical topic in AIDS research: natural cell proteins capable of preventing an HIV infection from taking hold in animals, and how these factors might be exploited to block HIV in humans.
In the Science paper, amfAR fellow Theodora Hatziioannou, amfAR-funded scientist Paul Bieniasz, and colleagues at the Aaron Diamond AIDS Research Center modified two such host resistance factors, TRIM5 and APOBEC3G, to create a monkey model for human infection. Previously, such animal models for investigation of AIDS vaccines and drug therapies had to rely on the monkey AIDS virus called SIV. But SIV differs from HIV in many key ways, greatly limiting its applicability to human disease. In this new work, about 10% of the genetic material of a standard HIV strain was replaced with sequences from the monkey AIDS virus core (or capsid) and Vif genes, enabling it to grow robustly in both human and monkey T-cells.
The authors predict that these relatively small changes they made in HIV should be sufficient to allow cross-species transmission, as well as “facilitate the development of new therapies and vaccines” in monkeys infected with it.
In the second paper, amfAR-funded fellow Ya-Lin Chiu, working at the Gladstone Institute at the University of California, San Francisco, focused on the APOBEC3G protein. Utilizing highly sophisticated techniques in molecular and structural biology, Chiu and colleagues studied how different forms of this protein could protect cells from infection with retroviruses such as HIV and SIV, as well as from retrovirus-like genes that are embedded in the genetic structure of all animals, including humans. The latter can also cause serious damage to a cell, through a process known as genomic instability, unless kept in check.
Chiu and associates noted that these two functions of APOBEC3G—protecting against infections from without (by retroviruses such as HIV) as well as “threats from within”—differed depending upon whether a cell was activated or resting. They then offered a clever strategy to preserve both functions in any cell, regardless of its activation state, through modification of the ability of ABOPEC3G to bind to certain nucleic acids.
It is this type of innovative work, spearheaded by the Aaron Diamond and Gladstone groups and supported by amfAR, that offers clues to the development of new classes of anti-HIV drugs that are based not on chemicals to attack viral proteins, but rather on natural cellular factors.
Dr. Laurence is amfAR’s Senior Scientific Consultant.