“The paper basically presents the first coherent evidence concerning the mechanism of function of the critically important viral infectivity factor (Vif protein) encoded by the human immunodeficiency virus type 1 (HIV-1).”

The paper basically presents the first coherent evidence concerning the mechanism of function of the critically important viral infectivity factor (Vif protein) encoded by the human immunodeficiency virus type 1 (HIV-1). The data shows that Vif binds to a recently discovered antiviral cytidine deaminase called APOBEC3G and causes polyubiquitination and efficient degradation of the latter enzyme. This eliminates APOBEC3G from HIV-1 infected cells and precludes its inactivation of the virus. It is important to understand that human lymphocytes (the major viral target) have an innate means to destroy HIV-1 that is neutralized by Vif, and that innate immunity is a major frontier in virus research. An understanding of Vif provides new strategies to screen and identify novel drugs against AIDS. The paper is widely cited because it bridges all of these important issues.

The Vif-APOBEC3G discovery, which has been elucidated also by many other laboratories, provides an exceptionally clear example of innate immunity and the mechanisms that viruses employ to defend themselves. These insights are being applied to understand other viruses, including hepatitis B and endogenously inherited retroviruses and retroelements that comprise a substantial fraction of human DNA. The Vif gene is necessary for HIV-1 replication in patients, and efforts to inhibit it with drugs are very promising.

The cells in which HIV-1 replicates have a previously unrecognized and highly evolved defense system to destroy the virus and its relatives. HIV-1 uses Vif as its sword to eliminate the defense system and to create a safe nest to form its viral progeny. If Vif could be inhibited by a drug, the powerful innate healing system that has evolved for millions of years might be unleashed. Thus, the overall research in this field has unveiled a new strategy to combat AIDS.

Until about 1998, we were working only on unrelated aspects of virus diseases. However, a student in my lab, Navid Madani, and I realized that Vif was a critically important protein that had been largely neglected because of its complex and confusing effects on different cells. We decided to do a simple experiment that might clarify Vif's role. Simultaneously, similar studies were ongoing in Michael Malim's laboratory, and our concordant results strongly indicated that Vif's job is to neutralize a potent antiviral defense system that is potentially capable of destroying Vif. Once we realized that a novel intracellular defense system existed, we were hooked and haven't stopped. Malim's group subsequently identified APOBEC3G as a component of the intracellular defense system, and by then we had the tools to make our additional contribution.

The work in my lab was done in a collaborative manner by three excellent individuals. Mariana Marin is a postdoctoral fellow who was originally from Romania and received her Ph.D. in France. Kristine Rose is a graduate student, and Susan Kozak is a Senior Research Associate.