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Being Alive

HIV Pathogenesis: The Evolving Understanding of HIV Disease


Being Alive 1995 May 5: 2

(An interview with Dr. Michael Saag, noted AIDS researcher and Associate Professor of Medicine and Infectious Diseases at the University of Alabama, Birmingham.) * What is HIV Pathogenesis? Generally, pathogenesis refers to the concept of how HIV causes disease. In the case of pathogenesis of HIV, it is a formal study of what HIV does to weaken the immune system, and how it interacts with the host to ultimately lead to a state of advanced immune suppression referred to as AIDS. This is important because, in any disease process, when you think about treatment, it's always best to understand how the virus is causing the disease or how the process is occurring. Once you understand that, then the approach to therapy can be much more rational and targeted, rather than just a trial and error approach, where we'll initiate something and see if it works or if it doesn't work and just move on. When you understand the disease process better, then the approach to treatment becomes much more logical and treatment outcomes become better.

* You recently reported that the immune system and HIV are in a state of all-out war almost immediately upon infection. Didn't we already know that the body was fighting back against HIV? We've known that the body responds to HIV and that's not really much of an issue. HIV-antibody tests like ELISA and Western Blot have been available for over a decade now and they tell us that the immune system recognizes that something foreign is there and is trying to respond to it. But that hasn't told us why the immune system weakens over time. The immune system responds to all kinds of invading pathogens and doesn't end up in a state of advanced immune suppression or immune insufficiency. In this disease, somehow, that was happening, so we wanted to study further what the virus does from the beginning. Now we know that the body has been fighting back all along. What we have gained is a deepened appreciation of how effective that fight really is, and that the fight is going on every second of every day that someone's infected.

* If the body is doing so much to fight the virus, what eventually tips the balance in favor of the virus? I don't think we know that precisely. I can give you some guesses. In the simplest terms, I think the virus has just two missions in life-to survive and replicate. It will do everything possible to achieve those goals. On the other hand, the immune system's role is to keep the virus from replicating as much as possible. The immune system does that very well throughout most stages of HIV disease.

New studies have shown us that the virus replicates at an extraordinary rate, producing around one hundred million new viruses per day in virtually any stage of disease. With that kind of replication, the body responds by having the CD4 cells (a type of white blood cell) and the rest of the immune system fight back. It produces around a billion new CD4 cells a day but is probably losing that many as well, so there's this constant battle between the immune system and the virus. Over time, the virus begins to win in a war of attrition and the immune system ultimately just wears out in its ability to keep the virus fully at bay.

* What are the implications of these recent findings when it comes to treating people with HIV? There are several very strong implications. The first is that I think we've gained a very deep appreciation for patients with advanced disease with very low CD4 counts. Their bodies still continue to fight the virus up until the day they die. I think there has been a tendency among a lot of treaters to give up on patients in later stages of disease. This gives us a new, fresh look at those individuals and says no, we should continue aggressively to try to find ways to help the immune system fight the virus, even in the advanced stages. That's one implication.

The second is in the opposite direction. If we gain this appreciation that the viral turnover is enormous even in early stages of disease and that the immune system-viral battle is occurring from day one, it makes more and more sense to treat the infection early as well as try to help the immune system out while the balance is still in its favor by suppressing that replication with antiviral therapy.

The third thing is that we recognize more than ever that it really is the virus that's primarily responsible for disease progression. There has been a lot of talk about, "Gee, maybe the virus stimulates the immune system to attack itself and there's an autoimmune process going on." There may be some of that happening, but by far the number one thing that's going on is that the virus is replicating to an enormous degree. Whatever we can do to keep the viral burden low, to keep that replication at a low rate, is going to be ultimately in favor of the patient. So our mission, when we treat patients at any stage of disease, is to keep the amount of virus in the bloodstream, or the amount of virus being produced daily, as low as possible for as long as possible through whatever means we have available, and the best approach to that is with anti-retroviral therapy.

* Would you say that it's more important to focus on suppressing viral replication than strengthening the immune system? Yes. The primary focus ought to be inhibiting the virus. That doesn't mean that we can't develop adjunctive therapy, immune-based therapy that might help bolster the immune system somewhat. It's striking how well the immune system can bounce back with responsive CD4 cells, etc., in some of the patients that have been treated with more potent combinations of antiretroviral agents. So whatever we do, we first and foremost need to treat the virus. Then we can think about immune system stimulation as a secondary objective.

* Does that affect our use of drugs we have available right now, like antiretrovirals? Do you think that these drugs can be used more effectively given our new understanding? Absolutely. We're becoming more and more entrenched in the approach of not using monotherapy, or a single agent. I think this virus is too resilient. It replicates too rapidly, and there are too many mutants that exist within an infected individual that are going to be resistant to any given single agent. No matter how potent the agent is, I think it's unrealistic to expect a single agent to work, especially from existing therapy. So the first take-home point is that monotherapy should only be used for a limited duration and we should move rapidly into combinations of agents. I think that, again, the notion that we should be using them in combination earlier is something we're coming around to.

* What's your sense of how new drugs on the horizon, things like protease inhibitors, will fit into treatment strategies given this new understanding? I think in two ways. One is that patients who have already been through a number of the regimens now have something new to turn to, even in combination with their previous monotherapies that may have failed as monotherapy. That drug may be effective in combination with a protease inhibitor.

The second thing is that it underscores something I've been saying for a long time, and that is the notion that treating earlier in this infection is predicated on the belief that better therapies will be available down the road. If we believe that science and man's knowledge will lead to better agents and better approaches to treating this infection, then we ought to be treating early and aggressively, playing the cards we have and hoping that newer agents will become available. The protease inhibitors are good examples of how science has produced new approaches to treatment that seem to be adding something that patients can move to after they have been through other treatments. So it underscores our ability to produce new agents and to reinforce the belief that, over time, better agents and better combinations will be available.

* Why do the drugs we already have lose their effectiveness over time? The primary reason in most instances is that the virus mutates and becomes less susceptible to the agent that's being used. That's a function of two things: the enormous viral turnover rate and the virus's tendency to mutate. When you put those two things together, you have an enormous potential for viral mutants that could be resistant to a given regimen or agent. When you apply the pressure selectively, that is, you give a patient a drug and then that drug starts to suppress the susceptible population, the resistant virus starts to emerge, leading to loss of effectiveness in most agents.

* What treatment strategy would you advise for somebody who's just found out he or she is HIV+? Let the immune system carry the fight initially and use drugs once the balance begins to tip toward the virus, or begin treatment immediately? This is obviously a judgment call. My personal viewpoint would be to lean toward treating early, before the immune system begins to weaken. The immune system is at peak efficiency in earlier stages of infection and it's really doing a good job of keeping the virus at bay.

To use a military analogy, if the immune system is the infantry, giving air support to the infantry makes a lot of sense even when the infantry is strong. I think that we should be treating early and I would lean toward treating a newly identified patient earlier rather than waiting for the immune system to fail.


Information in this article was accurate in May 5, 1995. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.