The following is a transcript of a press conference that took place at CROI 2008, one of the most important HIV-related medical conferences of the year. In this transcript, Mario Stevenson, Ph.D., of the University of Massachusetts Medical School, previews studies on the next generation of HIV medications in development. The studies he highlights focus on two topics: 1) medications that may be able to stop the entry of HIV into host cells; and 2) medications that may be able to slow or stop the progression of HIV disease.

HIV is a very simple genetic unit. It has nine genes. We as humans have 30,000 or so genes. For this reason, viruses can't survive on their own genetic material, so they have to commandeer components of the [host] cell. They have to commandeer cellular proteins to complete certain aspects of their life cycle. Up until last month, there were a handful of cellular cofactors that have been shown to help HIV replicate. Perhaps the most important was a receptor called CCR5, which the virus uses in order to gain entry into cells. Because of that basic research discovery, we now have small molecular inhibitors that block the ability of the virus to bind to this receptor, and they are now being used in the clinic to treat HIV infection.

In the last couple of weeks, we were all amazed by a publication from Abe Brass and colleagues that presented evidence for 200 more cellular cofactors of HIV replication.¹ These are 200 additional potential points of interception, and therapeutic intervention. So, now the work starts, in terms of finding out which of these 200 new proteins are actually going to be the most important for the replication of HIV and are going to be targetable from a therapeutic standpoint.

While we know that there are cellular proteins which help the virus, it's now become apparent that there are some cellular proteins which block the ability of the virus to replicate. If these proteins block the ability of the virus to replicate, why do people still get infected? The reason is that HIV has evolved a counter-defense against some of these proteins, what we call cellular restrictions.

It now looks like a lot of the virus's genetic effort is actually geared towards protecting itself. Of the nine genes that the virus possesses, three of those genes appear to be there solely to act as a counter-defense that the virus uses to protect itself against these cellular restrictions. One of these proteins, a protein called Vpu, has long been known to be important for the ability of the virus to egress from the cell. So when the virus is manufactured in the cell, it has to physically detach from the cell in order to enter biological fluids and be passed on to the next target cell. So this viral gene Vpu was of a purely defined function.

This month, a paper from Paul Bieniasz's group at the Aaron Diamond AIDS Research Center has identified a cellular protein which is negated by the Vpu protein. This cellular protein is called CD317, or tetherin. This protein apparently prevents the detachment of the viral particles from the cell.² In the presence of this cellular protein tetherin, particles stay stuck on the cell surface. Of course, that's not good for the virus, because the virus has to leave the cell to go on and initiate infection of a new cell. To circumvent this tetherin block, the virus has evolved a Vpu protein, and it looks like the viral Vpu protein simply targets tetherin for destruction, thereby removing the block to particle production.

So again, this represents a novel therapeutic target, because if we can find ways to block the viral Vpu protein, then we can stop the spread of the virus beyond the cell that's actually making particles.

I'd just like to also [spend] a couple of minutes on important discoveries being made into the mechanism of AIDS pathogenesis. There's still a lot to be learned about how viruses like HIV actually cause disease. We know the virus kills CD4 cells. We know the virus causes immune deficiency, leaving the host open to opportunistic infections. But the actual underlying mechanism behind pathogenic infection is still an area of great investigation. At the conference there are going to be several presentations -- I think five in all -- that will make the case that the virus is destroying a critical subset of CD4 cells. A subset apparently is very important for fighting off bacterial and fungal infections. When the body loses the subset of cells, called TH-17 cells, the body no longer has the ability to prevent these pathogens from activating the immune system, from replicating and activating the immune system. That's bad for the host and good for HIV, because HIV thrives on immune activation. When cells become activated, the virus has more permissive substrates for replication.

So the translocation of bacterial microbial products into the tissues, and the loss of these CD4 cells that would normally control those pathogens, may generate the immune activation as a hallmark of pathogenic HIV infection, creating conditions for disease progression.

So now we have targets in viral-host interplay and we have targets that potentially could lead to therapies which circumvent and which truncate the progression of the disease.

Footnotes

1. Brass AL, Dykxhoorn DM, Benita Y, et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science [serial online]. January 10, 2008.
2. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. January 24, 2008;451(7177):425-430.

This transcript has been lightly edited for grammar and clarity.