Keeping HIV Out of a Cell’s Nucleus

By Rowena Johnston, Ph.D., and Jeffrey Laurence, M.D.

April 16, 2010 -  One characteristic that makes HIV infection particularly insidious is the ability of the virus not just to insert itself into the cells of its human host but to integrate itself into the DNA at the core of those cells, thereby making itself a permanent part of the person it has infected. Once inside the DNA, the virus can make copies of itself and cannot be killed unless the cell in which it resides is destroyed.

Dr. Zandrea Ambrose

Writing in the April issue of the journal Cell Host & Microbe, amfAR fellow Dr. Zandrea Ambrose sheds new light on how the virus finds its way into the nucleus of a cell, the first step in its DNA integration. Dr. Ambrose, working first at the National Institutes of Health’s HIV Drug Resistance Program and now at the University of Pittsburgh, together with colleagues from across the U.S. and Japan, focused on an aspect of the integration process that has puzzled scientists for years, namely the very large size of the virus’s genetic material relative to the passage it must traverse. 

After entering a cell, the virus assembles itself into a preintegration complex, or PIC, consisting of its own genetic material and a number of proteins. The entire PIC then must make its way to the DNA of the cell, inside the nucleus, by passing through pores in the membrane that envelops the nucleus. But the pores that allow the normal trafficking of cell constituents through the membrane are far too small to permit the passage of the PIC.  So the question is, how does the virus manage to gain access to the DNA inside the nucleus, and even more importantly, can this process be prevented?

amfAR-funded scientists and other researchers had shown that, as with so many other processes in the life cycle of the virus, HIV’s PIC must co-opt normal cell proteins to guide it. But, as Ambrose and her colleagues note, exactly how this happens remains unclear. Uncovering those details may point to new ways of attacking HIV.

Part of the answer to the puzzle lies in the fact that the PIC must be actively chaperoned through the nuclear membrane, rather than relying on passive diffusion. In order to do that, the PIC must interact with a normal cell protein belonging to a class known as nucleoporins. Now Ambrose and her colleagues have identified a specific region of a nucleoporin that must interact with a single amino acid of the core shell or capsid protein of HIV to enable nuclear entry. Better yet, they also found that a fragment of a cellular protein known as CPSF6 can block the interaction between virus capsid and nucleoporin, preventing HIV from entering the nucleus.

As Ambrose and colleagues noted, many other cell proteins appear to be involved in the nuclear journey of HIV. Future research will help identify many additional ways to halt its progress.  

Dr. Johnston is amfAR’s vice president and director of research and Dr. Laurence is senior scientific consultant.