Being Alive, Los Angeles; Feburary 1998
Walt Senterfitt

The eradication hypothesis predicted that if you take the drugs long enough for all the old infected cells to die their natural deaths, then the immune system would be rebuilt with new uninfected cells. These uninfected cells would be protected by a continuing adequate dose of combination antiviral therapy until the last of the HIV dies out. Then one could theoretically stop taking the drugs, and HIV would not come back. Even though only a hypothesis, this rationally-founded hope has helped motivate tens of thousands of asymptomatic HIV+ people to take a handful of pills everyday, pills which may cause annoying-to-obnoxious side effects and which definitely require rigorous attention to meet their demanding "adherence" schedule.

Even the most enthusiastic promoters of this theory, however, were always careful to point out that it rested upon the assumption that every HIV-infected cell did indeed have a natural lifespan, after which it would die and be replaced. This lifespan is measured by observing the cellular "half-life," the time by which half of all cells of a particular type die. Researchers admitted that we were only just beginning to learn about the life cycle of some of the more uncommon and inactive cells of the immune system.

The original estimates of first one year, then three years, then six years for eradication to be completed were based upon the evolving knowledge of the life cycle of the most common (and therefore most studied) immune system cells. The T-cells or CD4 cells circulating in the blood or trapped in lymph nodes are the first to go, in a matter of days. This is why 99+% of all HIV can be eliminated in about two weeks of effective combination therapy in most people. When this happens, the viral load in the bloodstream becomes "undetectable." The next group of cells to die (sometimes called "the second compartment") are the macrophages and other lymph tissues like the tonsils and the protective patches found on the inside lining of the intestinal walls. These cells take months rather than days to be replaced.

Problems In the Third Compartment

As we reported in October, 1997, Dr. David Ho and others targeted the so-called "third compartment" as the area where problems in eradication seem to be most worrisome. (Earlier fears about possible "viral sanctuary" sites, such as the brain or the testicles, where antiviral drugs could not easily penetrate, have diminished considerably.) The "third compartment" refers to the longest-living immune system cells which can be infected by HIV: the resting CD4 cells or "memory cells." These cells are few in number and are seldom activated, making their behavior very difficult to study. They are crucial to the body, however, because they contain the body's arcHIVes or memory of all the infections it has conquered or controlled earlier in life.

Three Discouraging Studies Published In November

Three studies were published in November which, at a minimum, document how difficult it will be to eradicate HIV from this third compartment. Some scientists, as well as most of the popular press, took these new studies as the death knell for the hope of eradication.

Why were these studies so important? They each showed that CD4 cells capable of reproducing HIV can be awakened from their resting state, even after two years of the most effective antiviral therapy now possible. The researchers took resting or memory T-cells from volunteers whose viral loads had been undetectable for up to two full years, measuring them with the newest ultra-sensitive viral load assays. This answered one key question: is the HIV hidden in resting memory cells capable of reproducing itself and spreading to other T-cells when that resting cell "wakes up?" Answer: unfortunately, yes, at least under laboratory conditions made highly favorable for the virus.

The next piece of bad news from these studies was that these resting memory cells do not show evidence of naturally dying off at all. Specifically, when comparing samples of blood taken from a volunteer immediately after he or she became undetectable to samples taken every few months up to two years later, there was no measurable decrease in the numbers of HIV-infected cells over time. Ho and the optimists were prepared for this third compartment to have a very slow rate of "decay" but not for no rate of decay at all!

There was also good news in these studies, however. For one thing, the numbers of resting memory cells infected with HIV capable of reproducing is very, very small: 0.0002%, or two out of every million. Some optimists say that if this tiny number remains the same after several years of antiviral therapy, perhaps the body's natural immunity is able to take care of them when they activate. Even Dr. Ho has become more cautious about this possibility, though, saying "Don't count on it." Still, it stands to reason that a tiny number of something (assuming you can find 'em all!) is easier to kill than a ton of them! The other good news is that the virus which springs forth from these reactivated resting memory cells is not drug resistant, at least not to the combination which the person was on when s/he achieved and maintained undetectability. In a few cases, evidence of resistance to earlier monotherapy was found. This answered another key question positively for us: does a tiny amount of residual virus necessarily imply that some residual viral replication is going on? No (thank goodness!). This means that in these volunteers, which certainly represent the best-case scenario for presently-available therapy, the development of drug resistance was stopped absolutely cold! In other words, while these individuals may not ever be able to stop taking their drugs, they can expect that these drugs will continue being effective indefinitely.

What Does It Mean?

Some believe this information means the hope of eradicating HIV is now essentially gone. They regard the evidence as saying that memory T-cells live for the body's entire lifetime, that we can never expect to eliminate HIV once it is stored in this third compartment. The best we can hope for is lifelong control; no cure, but quite possibly the status of "chronic manageable disease."

Others, including Dr. Ho, are not so willing to give up. As quoted in last month's Newsletter, "Some would say it means eradication is not possible. But those of us who are working on the science look at [these November studies] differently, and say this is information we need to achieve eradication. Now, with this information, how do we move on? How do we flush that residual pool out, how do we protect the individual from that virus reactivating and spreading the infection?" Dr. Doug Richman of San Diego says, "Maybe ten years of therapy will be enough. Maybe these memory cells do decay and get replaced, just at a very, very slow rate that we have not yet been able to measure."

Several strategies are now being considered to eliminate this third compartment. One way is to deliberately stimulate the latently-infected resting memory cells so that potent combination antiviral therapy would prevent further cycles of infection. There are obvious dangers, such as the possibility of stimulating production of so much virus that it would overwhelm the power of antivirals to prevent new infection. Another danger is of producing such a magnified immune system activation that it would resemble toxic shock syndrome. (The immune system's normal responses of tissue inflammation and high fevers are what make the side effects of some immune-based therapies like Interleukin-2 or -12 so miserable, resembling a very bad flu. Some doctors feel that a immune system stimulation strong enough to blast out enough memory cells to make a difference, would have side effects so severe as to make those of the current IL-2 therapy seem a picnic.) From the perspective of common sense, I wonder if blasting out all the body's memory of previous exposure to other infectious agents might leave the body about as vulnerable as HIV-generated immune damage doesthe potential of throwing the baby out with the bath water.

Other investigators (I hope!) are speeding up their efforts to learn as much as we can about these resting memory cells and what happens if they are artificially stimulated. Would they be replaced? How effective would these replacements be?

In any event, the news has enough hope to be encouraging. The ability of optimal therapy to eliminate evolution, mutation and development of resistance in HIV is good news indeed. At the clinical level, and for community and self-help advocates, the immediate and exciting tasks are: to develop and hone tactics, to manage current drugs and those soon to be available, so that everyone can optimize her and his opportunities to stop resistance and thus prolong effectiveness indefinitely.

Of course, we need more antiviral drugs, which are better and easier to take and tolerate.

And the pendulum in research priorities and focus probably needs to swing back a bit from the virus to the immune system. David Ho started his lecture on eradication in Vancouver with a slide that read, "It's the virus, stupid!" That was an understandable payback to the Duesberg-ites, heal-ers and all the others who say HIV does not cause AIDS. Everyone who has gotten better (or has not gotten sick) while taking combination therapy would agree with Dr. Ho's assessment.

Yet, like most categorical statements in the history of science, that one-sided statement can fail to capture what is actually an indissoluble interaction, between host and parasite, between defense system and invader, between perturbation and equilibrium. While "It's the virus, stupid!" may capture one essential paradigm of the fight against the devastation that is AIDS, so does: "You know, stupid, it's the immune system after all."

For more detailed analysis of these issues by our best community "treatment wonks," I recommend Mark Harrington's article "The Twilight of Eradication" in the December 1997 issue of the Treatment Action Group's newsletter TAGline and Dave Gilden's article "HIV Resurrection" in GMHC's newsletter Treatment Issues of November 1997, available in the Being Alive library.

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