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AIDS Treatment News
New Information on HIV Rapid Turnover - What Does It Mean?
John S. James
January 20, 1995
AIDS TREATMENT NEWS #215, January 20, 1995

On January 12, many newspapers carried page-one stories about a major scientific advance in understanding AIDS. Some of the reporting has been unclear and confusing to readers, however. This article will outline what the discovery is and why it is important to people with HIV or AIDS. We will also explain our concern that this new understanding, while indeed important, shows signs of being misunderstood in ways that could seriously harm AIDS research.

The occasion of the recent press coverage was the publication of two articles and a commentary in the January 12 issue of Nature,(1,2,3) which is one of the most prestigious scientific journals. The two articles are by two well-known research groups which independently arrived at essentially the same conclusions. AIDS researchers worked with mathematicians to help them reach a deeper understanding of the data -- which came from blood tests of patients with advanced HIV disease as they started taking certain experimental antivirals in small clinical trials.

The discovery announced in the newspapers on January 12 was not news to the scientific community, which has heard the central idea at a number of public conferences during the last year. We published a preview last November, in an extensive quote from Douglas D. Richman, M.D., who spoke on November 12 to a physicians' conference in San Francisco (see "Viral Load, Small Trials, and Immune Recovery," AIDS TREATMENT NEWS #211, November 18, 1994).

New Understanding of HIV The new understanding of how HIV behaves in the body was made possible by the development of better antiviral drugs, which can now shut off HIV reproduction almost completely (although so far only for a short time since resistant virus develops in a few weeks) -- and also by the new blood tests which measure plasma HIV RNA, a much more accurate indication than the old p24 antigen tests of how much virus is in the blood. The three antiviral drugs used were the Abbott protease inhibitor (ABT-538), the Merck protease inhibitor (L-524, also called L-735,524), and Boehringer Ingelheim's nevirapine (which is a non-nucleoside reverse transcriptase inhibitor); all three of these drugs are experimental and currently in clinical trials. AZT, ddI, and other approved anti-HIV drugs do not stop the virus well enough to make the new discovery obvious. [Note: the HIV RNA blood tests used are today available to physicians; for background, see "HIV RNA: New Blood Tests for Individualized Therapy and Faster Trials," AIDS TREATMENT NEWS #204, date August 5, 1994, and later issues.] Both the research teams measured the HIV RNA frequently (at least weekly) when patients started taking the new experimental antivirals. They found that once the reproduction of new virus was shut off, the viral level in the blood declined very rapidly; about 30 percent of the virus is cleared from the blood each day (and this percentage may be about the same regardless of stage of the disease). Since blood levels are fairly stable from day to day when the patient is not taking an antiviral, about as much new virus must be produced every day as is destroyed. The essence of the new discovery is that the "turnover" of new virus in the body is far more rapid than people had believed -- in just a few days, most of the virus in the blood has been removed and replaced with fresh virus.

Also, these drugs work by stopping the infection of new cells -- not by shutting off viral production from chronically infected cells -- and still they often cause the amount of virus in the blood to drop by 99 percent or more. This means that almost all of the enormous amount of virus being produced continuously during HIV infection is coming from newly infected cells.

The researchers also measured the recovery of CD4 cells (T- helper cells) while the reproduction of HIV was temporarily shut off. They found that CD4 cells increased very rapidly during this time. This seems to mean that they are also being destroyed equally rapidly when the virus is not shut down. (Although an alternative possibility, which we do not believe is ruled out by the new Nature articles, is that active HIV infection produces something that suppresses production of new CD4 cells; if this is the case, CD4 cell turnover in HIV disease may be less than now thought.) [Note on terminology: Until now AIDS TREATMENT NEWS has preferred the term "T-helper cell" to "CD4 cell," as being better for communicating with the public. But now the more accurate term "CD4 cell" (or "CD4+ cell," which is the same thing) is coming into wider use, and will be our preferred usage in the future.] Through simple calculations based on this data, the researchers estimated that about 100 million virions (individual virus particles) are normally being produced and destroyed each day. (Note that this applies only to patients with fairly advanced HIV disease, who were studied in this research; they had a median CD4 count of 102 in one of the papers, a mean of 180 in the other. In earlier stages of asymptomatic HIV infection, the number of virions would usually be much less.) Also, the researchers estimated that about two billion CD4 cells are also being created and destroyed each day in these patients. Each infected cell can produce many copies of the virus; the researchers suspect, therefore, that most infected CD4 cells are destroyed by the immune system before they ever have a chance to produce complete virus.

Importance These findings are important to people with AIDS/HIV because: * They strongly suggest that if HIV reproduction could be largely stopped for a longer time, and kept at a very low level indefinitely, then the immune system would have much more ability to recover, even without immune-based treatment, than most physicians and scientists had believed.

Note that this does NOT mean that the virus will be eradicated. Huge reservoirs of latent virus will still likely remain, in the DNA of cells in lymph nodes and elsewhere. While it is latent, it is not doing damage. But some of the latent virus may become activated later and re-establish the active infection. It will probably still be necessary to take drugs to keep the virus suppressed -- although if the immune system recovers, it may be an important help in this process.

* It is now clear that researchers can test potential antiviral drugs and combination treatments in people in small, rapid trials -- which get results in weeks. This means that it is feasible to test many new treatments quickly, greatly speeding the development of better AIDS/HIV treatments.

Of course it will be necessary to continue testing the treatments which do show antiviral activity, to see how long they work before viral resistance develops. This should not be hard to do, since patients will naturally want to continue taking a treatment which is working.

Other steps are also necessary before FDA approval. [We analyze the critical bottleneck in the whole process -- the need to prove actual clinical benefit to patients -- in "1995 Outlook -- Research Strategy," below.] * They emphasize again the major problem of HIV developing resistance to drugs. The very rapid turnover of HIV in the blood means that in just two to four weeks, the drug- susceptible viral population in a patient can be replaced by a drug-resistant population, meaning that the drug will no longer work, or at least not work as well.

The researchers emphasized the need to use combination treatments to prevent drug resistance. Drug combinations help to prevent resistant viruses from developing, because only a small fraction of the virus will initially be resistant to any candidate drug. If a second drug is added, only a small fraction of that small fraction will be resistant to both. The more drugs that are added to the combination, the less likely it will be that any virion will be resistant to all of them. But with billions of virions in the body, it may take a number of drugs in combination to stop all of them.

Some researchers have suggested that combination treatments should be used early in infection, when the viral load in the body, and also the variation of the virus, is less. (It is generally believed that HIV infection starts with only one variant of HIV, but as the disease progresses, this one strain evolves into a great many different "quasispecies" within the individual patient. In each patient, this evolution is different.) Comment: What This Discovery Does Not Explain The most important unanswered question about HIV disease may be how it progresses from early, asymptomatic infection to late-stage illness. For years the immune system controls the virus to a degree, and blood levels stay relatively low. But somehow the body gradually loses this ability (in most people, but not in all), allowing the virus in the blood to increase by as much as hundreds of times, leading to the development of AIDS.

Many theories have been proposed to explain how HIV suppresses the immune system -- including, for example, direct killing of CD4 cells, and also indirect mechanisms such as molecular mimicry, cytokine or possibly endocrine dysregulation, autoimmunity, abnormal apoptosis, loss of CD8 cells, etc. If researchers knew why the immune system gradually loses its ability to control HIV, then it might be possible to treat HIV infection by correcting this specific problem, and keep people healthy indefinitely, perhaps without the need for antivirals.

We are concerned by indications that some researchers, as well as medical reporters, may uncritically assume that the new understanding of HIV also explains how the infection progresses from the early, asymptomatic stage, to the later stages of greatly increased HIV levels and clinical illness. Such a premature conclusion could suppress interest and research in other potential mechanisms of progression.

The new information recently published in Nature was based only on studies of persons with advanced HIV infection. And each patient was studied only for a brief snapshot of time; there was no long-term data on how infection progresses over time.

The Nature papers do not claim to have shown how HIV infection progresses. But they are often being implicitly interpreted that way. Some of these interpretations do not stand close scrutiny: * One assumption is that, due to the great number of CD4 cells infected and destroyed, the immune system eventually becomes exhausted and unable to keep up, and then the disease progresses because the body cannot produce enough CD4 cells to replace those that are lost.

But this theory ignores the fact that HIV disease progression occurs also at earlier stages, when the level of HIV infection and destruction of T-cells is a small fraction of what the body will be able to keep up with later. For example, there is data showing that in persons with a CD4 count around 200, the level of virus in the blood may be ten to a hundred times more than the level when the CD4 count is 500.(4) How could this exhaustion theory explain the progression from a CD4 count of 500 to 450 or 400, if at 500 the body still has at least ten to a hundred times the capacity needed to replace the cells which are lost at that stage? * Another assumption -- seen repeatedly in the January 12 New York Times article -- is that HIV infection progresses because the virus has a "slight statistical edge" over the immune system, leading to its eventual victory. But this theory is unlikely to hold up to an analysis of the dynamics of stability vs. instability. The levels of both the opposing sides in the battle -- the virus, and the CD4 cells -- can change greatly in a time frame of days or weeks. It seems unlikely that these two opposing forces, which each can change in days, will just happen to stay approximately balanced for the much longer time period of years that it takes for HIV disease to progress.

To visualize the problem, imagine an acrobat on a high wire who momentarily loses balance, and fights in an attempt to regain it. Usually only seconds will pass until either balance is regained, or the acrobat falls off. We do not expect to see the struggle go on for ten years.

In other words, some mechanism other than a slight statistical edge must be controlling the timing of HIV disease progression. No one knows what sets this clock; it should be a central goal of AIDS research to find out. The statistical-edge theory, by giving false confidence that the answer is already known, could distract research from this key goal.

Note that in most viral and other infections, the dynamics of the interaction between the replicating organism and the immune system does not lead even temporarily to a homeostasis, to a balance or steady state. Instead, the immune system either eradicates or almost eradicates the disease-causing organism, or the infection progresses until the person dies. (Nor does the limited supply of cells to infect explain the limited growth of HIV, except perhaps at end-stage illness; at earlier stages, the supply of CD4 cells would clearly allow more viral growth, as shown by the fact that viral levels will substantially increase later, when there are fewer such cells available.) No one knows why HIV reaches a certain blood level and then stops (until the level changes over months or years). When we discover the mechanism by which this control becomes established and maintained, but then gradually lost, we will very likely have a new way of controlling HIV disease.

* One of the recent Nature articles(1) noted, "The difference in lifespan between virus-producing cells and latently infected cells (PBMCs) suggests that virus expression per se is directly involved in CD4+ cell destruction. The data do not suggest an 'innocent bystander' mechanism of cell killing whereby uninfected or latently infected cells are indirectly targeted for destruction by adsorption of viral proteins or by autoimmune reactivities." We are concerned that readers may take away from this statement something different from what it actually says. While the data cited may not support indirect mechanism for the decline of CD4 cells, they do not rule out such mechanisms, either. Again, our concern is that important research could be prematurely downgraded or closed off, due to the rush of enthusiasm which has greeted the new findings.

(And if it turns out that active HIV infection somehow suppresses development of new CD4 cells, or suppresses their release into the blood -- and CD4 counts increase rapidly when the infection is stopped, not because they are usually being created and destroyed that fast, but because the suppressive effect is removed -- then the whole issue of the turnover and lifespan of infected CD4 cells will have to be rethought.) Research Strategy Summary The most important impact of the new understanding of HIV disease, published in two articles and a commentary in the January 12 Nature, will be on the strategy of research and development of new AIDS treatments. We see the following consequences: * The new work validates the use of small, rapid screening trials, in a few patients, to learn which potential drugs have antiviral activity in people.

* It also shows that if the virus can be suppressed completely enough, the immune system has much more ability to recover than many had suspected.

* It also confirms the belief that overcoming drug resistance is likely to be the biggest challenge to making anti-HIV treatments work.

* On the minus side, possible misinterpretation of the new findings (in the current atmosphere of great attention and enthusiasm for them) may impede important work of learning how HIV infection progresses -- work which could lead to a completely different class of treatments which do not attack the virus directly, but preserve the immune system's ability to control it.

References 1. Wel X, Ghosh SK, Taylor ME and others. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. January 12, 1995; volume 273, pages 117-122.

2. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, and Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. January 12, 1995; volume 273, pages 123-126.

3. Wain-Hobson S. Virological mayhem. Nature. January 12, 1995; volume 273, page 102.

4. Phillips AN, Sabin CA, Elford J, and others. Viral burden in HIV infection. Nature. January 13, 1994; volume 367, page 124.