Being Alive; April 1997
Walt Senterfitt

Let me be perfectly clear: there is no cure for aids yet. At January's Conference on Retroviruses and Opportunistic Infections, Dr. Ho clearly tried to dampen the misguided mantra of premature triumph, even as he presented somewhat encouraging experimental data. His punchline was (to paraphrase) "hiv has not been eradicated from anyone so far. New information has led me to project about three years of treatment as the minimum time to totally eliminate hiv from anyone's body, up from the one year that I told you last year. This is only for those who are able to start therapy within four months of being infected, and I am of course not yet sure if this is doable. I'm even less optimistic that we can eliminate it from those who have been infected for several years already. Nevertheless, here's the good news."

Background

Two recent developments made it possible to even raise the possibility of eradication without getting laughed out of the room. First, drug combinations are now available which can stop or nearly stop viral replication ("reproduction" or "multiplication," more or less) for at least a fairly long time. Stopping or nearly stopping replication is what an "undetectable viral load test result" means. Second, Dr. Ho and Dr. George Shaw of Birmingham, Alabama, discovered in 1995 that both hiv and the T-cells and other cells that hiv infects turn over at a much higher rate than scientists had previously believed.

We're talking really fast turnover. Individual hiv viruses (called "virions" or "virus particles") can only live 5 or 6 hours in the bloodstream. During this time, they either infect a T-cell or macrophage or they die. Once infected, T-cells become a producer of more hiv, These T-cells live on average only a day and a half, so that nearly all circulating, infected T-cells are dead within three days or so. When they are actively producing more hiv, T-cells are referred to as "productively infected." Dr. Ho estimates that about 99% of the hiv in the body at a given time is either in these productively infected T-cells or circulating as free virus.

Put these two developments together, and you can see how they came up with eradication theory. If we now have drugs good enough-in combination-to essentially stop hiv from infecting a new T-cell and taking over its nucleus (this is the part that the nucleoside analogs like 3TC, AZT, and the "d" drugs do) and to stop already-infected cells from manufacturing new hiv (the job the proteases do), then we can give the body time to replace all the T-cells with new ones which are "clean and sober," uninfected with hiv. Meanwhile, all the free floating hiv particles will die off or be killed by the body's immune defenses-they live just 5-6 hours after all. So the new uninfected T-cells will stay uninfected (assuming we don't get exposed to hiv from another person again!).

Problems With Theory and Practice

Sounds good. What's the problem, you might ask? Well, a big problem, and the one that led Dr. Ho to move back his minimum treatment time from one year to three, has to do with that other 1% of the hiv that is not circulating freely or in productively infected cells. The virus also infects macrophages and other immune system cells which are either trapped in the lymph nodes or are spread around the body in tiny patches that form a kind of first line of defense. These patches of so-called "lymphoid tissue" are located mostly in the mucous membranes of the mouth, throat, intestines and rectum and help trap alien organisms early, and alert the rest of the immune system to produce killer cells and antibodies that specifically target each particular kind of invader.

The lymph nodes trap clumps of infected cells and act both as a mechanical barrier to further infection and as a further sensory alerting device and manufacturing substation for the immune system. These macrophages, lymph nodes and diffuse lymphoid tissue are collectively referred to as the "second compartment of the immune system." The cells in the second compartment have a significantly slower rate of turnover than the T-cells; on average they live several weeks. A few may live for months or even years.

Even with completely stopping hiv replication, then, one must wait for the old infected cells to die and be replaced by new, uninfected cells. The process of hiv thus being eliminated is called "decay" of the viral activity, and it is measured in "half-lives." This is a concept from nuclear physics and mathematics that is used to describe the decline in radioactivity. Applied to hiv, the time it takes for viral activity or replication to be cut in half from the starting point is the half-life of viral decay. So, Dr. Ho found that the half-life of decline for free virus in the blood was 5-6 hours, of virus in productively infected cells 1.5 days, of virus in latently infected T-cells (that are not currently producing hiv but can and will do so once stimulated) was 8.5 days and from macrophages, 14.4 days. With a little effort perhaps, one can imagine that these short half lives mean that the viral burden comes down very quickly. But the fact that they are half-lives, leaving half still functioning after each interval, means it takes a long time for the viral activity to completely be eliminated.

Using just rough and linear calculations, say for macrophages, we can see that after two weeks, there's 50% reduction; after four weeks 75% (adding half of what was left after the first two weeks); after six weeks, 87.5%; after eight weeks, 93%; after 10 weeks, and so on. Eventually we may get all the way there, and maybe hiv replication essentially stops, by dropping below critical mass, even before every last smidgen is gone. Right now, scientists can only use mathematics to predict, and that is what led Dr. Ho to stretch out his estimates.

The human body behaves much less predictably than a uranium or plutonium atom. There will be a wide variation in the rate at which different individuals replace their immune cells. Obviously, the more damage one's immune system had suffered already when highly effective treatment was started, the less robust is a person's ability to fully replace the infected cells; thus the lesser optimism for those with long-standing infection compared to newer infections. Differences in viral strains, general health and other factors may further compound the variability. Still another problem is that the drug combinations have to continue working well enough in the person to effectively suppress all viral replication and to do so long enough for all this replacement to take place. We don't yet have precise enough tests to measure this nor enough backup combinations to use when drug failure is detected, though a lot of progress has been made.

The Good News

Dr. Ho and his colleague Dr. Marty Markowitz reported on the results thus far with 24 patients who were started on combination therapy within four months of becoming infected. Four have left the study because of intolerable side effects or noncompliance. Of the other 20, one was briefly noncompliant with treatment. After five months of treatment, all had attained undetectable viral loads (though the one briefly noncompliant patient had a viral load detectable by a sensitive research PCR test). No virus was able to be cultured from their T-cells or macrophages in the bloodstream, whereas all had culturable virus at onset of treatment.

Ho looked at the semen of five patients and was unable to find any evidence of infected cells or infectious virus. He did, however, find some virus fragments (proviral DNA) which he and most observers consider incapable of replication or development into a full virus particle. Some scientists disagree about the significance of these fragments of hiv DNA, underscoring once more that an undetectable viral load test does not mean that one is definitely noninfectious. Furthermore, he looked at lymphoid tissue from the rectums and colons of these five study participants. He used the most sensitive techniques available to find any evidence of active virus in these tissues. He found no infectious virus but he did find in three of the five some virus fragments usually associated with the replication process; he characterized these fragments as sort of hiv "building blocks" left over in some of these slow-turnover cells after treatment had shut down replication. Ho concluded that there was very little virus left in the lymph organs of these men, but that it had obviously not been totally eradicated.

In these recent infection cases, he also found evidence that the antibody immune response had been stopped short of the full blown type seen in patients at a similar stage of infection who have not started therapy. This may be additional evidence that very early treatment, if possible, can prevent even subtle changes and weakening in the immune system.

Given the new data about the slower than expected decay of viral activity in the second compartment, Dr. Ho plans to keep these patients on combination therapy for at least two to two and a half years more before offering them the option of experimentally stopping therapy to see in practice if the hiv has been eradicated. Before that, he plans to look closely at their spinal fluid to see if there is any evidence of remaining viral activity in brain cells. There is the possibility that the brain, and perhaps the testicles, are a "third compartment" where hiv may lurk in even more hidden ways.

Dr. Ho also presented data on eight patients started on similar treatment after having been infected for several years, though none had received prior antiviral therapy. The results were just about as striking in terms of elimination of evidence of actively replicating virus to be found in the bloodstream. Reductions in other lymph tissues were also striking, but less complete than in the recently infected people.

Questions Remain

Many questions remain to be answered. How thorough does suppression of viral replication have to be to get these results? What is the significance of the viral fragments found in the study patients? How closely can these results be duplicated in people who have had infection a long time and already been treated with drugs? Can virus in brain and reproductive tissues serve as a reservoir that could provide "seeding" for a new infection even if all other reservoirs have been completely drained?

Nevertheless, there is good news for all of us in Dr. Ho's work on this problem, even if it proves to advance no farther. Other studies supported his finding that reduction of viral load to undetectable levels in the bloodstream correlates with vast reductions of hiv in the lymph nodes and other lymph tissues. This was an open question until recently, and provides encouragement as to the probable durability of good responses to protease combinations. The reduction of infectiousness of the semen after effective antiviral treatment is also good news, even if it does not mean we can skip the condoms from now on. The data on rate of decay of viral activity and replacement of infected cells in the various compartments is new for everyone, and should help guide research in immune system restoration.

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