Click here to view next page of this article

 

HIV Pathogenesis

At this point in time there are about 16,000 new infections occurring on a daily basis. Ninety percent of these infections are occurring in the developing world. Over 50% of the infections are in young adults between the ages of 15 and 25. Only 10% of the HIV-infected people know that they are infected; 1600 children are being infected on a daily basis and more, at the time of this particular slide, more than nine million children have been orphaned by HIV infection of one or both of their parents. Clearly this epidemic is spreading unchecked in sub-Saharan Africa, on the Indian subcontinent, in Southeast Asia and the really truly remarkable advances.

Letís turn now to a discussion of what happens in the body when HIV infects. We know in fact that soon after HIV infection, in approximately 50% of patients, they develop a flu-like symptom complex. It is during this period of time that if you looked in the plasma you could find very high levels of replicating virus. Then the immune response to the virus occurs and the levels of infectious plasma viremia disappear to remain essentially at very very low detectable levels.

Now this picture of an early burst and a late burst of virus, with an intervening period of essentially of an eclipse, a viral eclipse, suggested that perhaps the HIV is not replicating at high levels during this period of time. That turned out to be incorrect. With the emergence of better tests to look at viral RNA we now understand that even during this period.

We also now understand from studies from George Shaw and David Hoís laboratory that in fact this is not a virus that is trickling along, a slow indolent infection. In fact we now understand, by taking advantage of the new sensitive assays of being able to measure viral RNA in plasma, and the availability of drugs that are capable of interdicting the replication of this virus, at least for brief periods of time, that this virus is turning over in plasma with a half-life of six hours. progenitors thymic function are also targets for HIV injury.

The other point I wish to make is that in fact when the immune system kicks in, it causes this drop in the level of viral RNA. Most people reach a certain kind of threshold, or certain balance, between how effective their immune response to the virus is and how vigorous the virus is replicating. We now know that this viral set-point is key. Because the level of that viral set-point is predictive of the subsequent clinical course expressed years later.

In terms of our therapy, there have been two major classes of drugs that have been shown to be effective against HIV. The first class of course were the reverse transcriptase inhibitors. Now reverse transcription is a key process in the retroviral life cycle in which this viral RNA.

The second target, which is really the combination of reverse transcriptase inhibitors and the second drug, the protease inhibitors, has led to truly remarkable effects. Now what does the protease do in the retroviral life cycle? It turns out that many of the proteins that form the core of the virus are in fact encoded for as one long protein which must then be cut by the protease.

The tremendous success of these anti-retrovirals is perhaps well shown here by the decline of opportunistic infections, be it pneumoniaís, Pneumocystis, dementia, all of these criteria of immune deficit has significantly improved in the post-HAART period. Indeed there was a suggestion that the combination of these reverse transcriptase and protease inhibitors were so therapy, using a variety of chemokines and cytokines.

So the other side of this infection, or the other dark news that is emerging. In this particular group of 136 HIV-infected patients who all were treated with a combination of potent antiviral therapy for a minimum of six months, remarkably only 47% of these patients are experiencing a

Reverse transcriptase, while this is the principal target, is one of the principal targets for antiviral drug development, in fact this is the viruses greatest defense against our therapies. By defense I mean, this enzyme is a crummy enzyme. It makes a mistake every time it replicates the viral

So where are the new targets? Well, there have been some significant breakthroughs in our understanding of the biology of HIV which have immediately suggested new therapies. The first breakthrough deals with the issue of how HIV gets into the CD4 cell in the first place. As many of you know, there has been a recently description of not only the role of CD4 as a receptor of HIV, but in addition, the participation of chemokine receptors. Seven trans-membrane receptor proteins as the co-receptor for HIV. Indeed, it turns out that the chemokine receptor is the principal receptor for HIV as I will show you in a moment. We know now that these chemokine receptors, which look like snakes coursing their way through the membrane, that HIV used two principal types of chemokine receptors for infection. It turns out that initial infection by

So why do I suggest that CCR5 is such a great target? Or such an attractive target for new drug development? Well, in fact, I suggest this because of an experiment of nature. It turns out that there are amongst us a few individuals who have a mutation, a 32 vase paramutation in

So if we could develop drugs against CCR5, small molecule inhibitors that would have essentially the same effect of being able to block HIV interaction with CCR5, we would predict first that we would block infection, and second that inhibition of CCR5 function really wouldnít lead to any untoward effects given the fact that these people with the mutation are alive and well and doing great.

An aside to this particular story was that issue that I mentioned in terms of the frequency of the genes in the Caucasian population. Looking at the prevalence of this 32 base paramutation in

Clearly every pharmaceutical company in the world now is working on the development of chemokine receptor antagonist with the intent of trying to block HIV entry. What about other potential points of attack in the retroviral life cycle, schematically shown here? Iíve talked about the reverse transcriptase inhibitors. Now a very logical point to try to interfere with this virus is that once the two copies of the DNA are made from the single copy of the RNA and that complex is imported into the nucleus of the cell, it is then integrated into the host genome. Into the chromosome. Thatís the third major enzyme of the virus, the integrase. Now several pharmaceutical companies have tried to target integrase but

In terms of REV, this is a regulator of latent structural gene expression. It turns out that REV has taught us so much about nuclear export it has revolutionized the area of normal nuclear export. By studying this viral protein we have gained insights into how proteins and RNAs get out of the nucleus and into the cytoplasm. Can we exploit that? Can we actually develop anti-REV therapies? In fact, gene therapy now with mutants

The final protein, regulatory protein, NEF. Well, it turns out that NEF has several roles. It enhances the infectivity of the virus, it down regulates CD4 but most importantly, in studies performed in monkeys, originally by Ron DuRocher and colleagues at Harvard, they were able to show that a cousin of HIV called the simian immunodeficiency virus, if they made simian immunodeficiency virus that was mutated in the NEF gene and gave this virus to monkeys, these animals developed no disease whatsoever, in contrast to animals that contained the wild-type NEF gene, these animals died of AIDS. Clearly NEF is critical for the pathogenic production, for the production of disease by SIV. The same situation has been encountered i

The attenuated nature of these viruses very much depends on their ability to produce disease. Very much depends on the immune and cellular environment in which they are acting. Certainly the ability of such attenuated viruses to produce disease in cases of immune compromise, raises serious safety concerns regarding an attenuated live vaccine for HIV, as has been

Iíd like to conclude with just a few comments about vaccines. Where do we stand in terms of vaccine development? Well, it turns out that the production of a vaccine against HIV is going to be a tough nut to crack. Mainly because we know that the virus can transmit freely, or from cell to cell without every going outside. We know that the virus targets the precise cells in the

So whatís happening in the vaccine arena? You may well have heard now that a phase 3 efficacy trial with the envelope protein of HIV is underway, sponsored by Vax-Gen, a private company based here in South San Francisco. Using an envelope preparation which has been