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
* 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
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
* 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
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
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
* Why do the drugs we already have lose their effectiveness
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
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.