AIDS TREATMENT NEWS Issue #206
John S. James

Despite the unknowns, there is more clarity today about HIV pathogenesis than is commonly realized. The developing knowledge will be useful for understanding the limitations of current treatments, and the requirements for better ones. This article looks at part of the evolving picture of HIV disease, focusing on aspects highlighted at the conference.

** Latent Infection Surprisingly Large

In a major plenary address, Dr. Ashley T. Haase of the University of Minnesota reported finding an "extraordinarily large" number of cells in lymph nodes and some other tissues infected by HIV early in the disease process. For example, 25 percent or more of CD4 cells in the lymph nodes were found to be infected; but only about one percent of those were actively producing virus at any one time. The others were latently infected; HIV had entered the cell and become part of its genetic inheritance, but because the cell was not activated, the HIV was not reproducing or creating abnormal proteins. These latently infected cells are undetectable by the immune system, since the HIV genetic information remains quietly inside the nucleus of the cell and does not affect the cell surface; for the same reason, this latent infection is undetectable by most laboratory methods. Dr. Haase's team used a special technique called in situ PCR; this causes PCR (polymerase chain reaction, which detects a particular DNA sequence by causing it to successively duplicate itself) to occur within each cell, allowing latently infected cells to be distinguished from uninfected ones in the laboratory.

This latent infection, a "Trojan horse," may not cause damage while it remains latent; but at any time some of the cells will become activated. Then more virus is produced, spreading the infection and/or killing the cell. The latently infected cells form a reservoir of virus which is not affected by the immune system, or by AZT or similar drugs; this reservoir enables the virus to persist, and may also be involved in transmission of HIV from person to person.

This view of HIV infection was not new at Yokohama, but grew out of several years of work at the Department of Microbiology of the University of Minnesota Medical School in Minneapolis; a major paper was published in 1993. (1)

[Comment: This information does suggest approaches to treatment, even though there are no known drugs which can selectively attack the latently infected cells, or the HIV genetic material within them. AZT, etc., and also the protease inhibitors, or other drugs which target various enzymes in the HIV life cycle, can help to prevent the infection from spreading into new cells; protease inhibitors might be better than AZT-type drugs for doing this, because they cause the newly-produced virus to be defective and non- infectious, while AZT, etc., only help block infection of new cells after it is already underway.

These antivirals can be combined with other treatment approaches which may reduce the amount of activation. Aggressive diagnosis and treatment of opportunistic or other infections can help, since infections increase the activation of immune cells.

Activation could also be reduced by various kinds of drugs. One example is immune suppressive therapies, which can be dangerous, but might be used in some cases, for example in early treatment, before serious immune deficiency has developed; or treatments might be used to reduce particular immune responses which are overactive. Various drugs are being tried to reduce abnormally high levels of TNF (tumor necrosis factor), which increase activation of HIV. Still another approach is to screen for drugs which inhibit the LTR (long terminal repeat) of HIV; it is now believed that certain CD8 cells inhibit HIV quite effectively by producing a substance (so far unidentified) which inhibits the LTR. Drugs to reduce activation are not likely to provide the whole answer, since some activation of immune-system cells is necessary for normal functioning; but reducing activation can be one of a number of approaches toward helping the immune system maintain or re-establish control of the HIV infection.]

** Major Lymph-Node Study Examines AZT, ddI Effects

DATRI-003 (run by the Division of AIDS Treatment Research Initiative, of the U.S. National Institute of Allergy and Infectious Diseases), is the largest study to date using lymph-node biopsies; 32 patients had two biopsies, eight weeks apart, and some of them started or changed treatment after the first biopsy. This study is important because HIV infection is especially active in lymph nodes. But some of the preliminary results are confusing or hard to interpret; we will know more when a full report is available.

All 32 patients had T-helper counts above 250, often much higher. They were divided into four groups. In group 1, patients had not had any antiretroviral therapy, and AZT was started. In group 2, there was no prior therapy, and none was started. In group 3, patients were already on AZT, and it was continued. In group 4, they were already on AZT, and ddI was added.

There was essentially no change in the percentage of infected cells in the lymph nodes of the different groups. (This result would be expected, as there is no reason to think that AZT or ddI could eradicate infection in cells where it was already established.)

Viral replication did decrease in the six patients who added ddI to their treatment (group 4); this was seen by measuring HIV RNA in both the lymph nodes and in the blood, although the decrease in the lymph nodes, which was seen in four of the six, was not statistically significant. Surprisingly, however, no effect was seen on viral replication in the lymph nodes in the group which started AZT -- although their T- helper count did rise.

One possible explanation of this difference is that those who started AZT began with a high T-helper count (mean 654), while those who added ddI begin with a mean of 394; the authors suggested that the antiviral effect of these drugs may be less in early disease. However, we would like to see the full report (which is currently being prepared for publication), since viral levels can be hard to measure in early HIV infection, even with the new tests. Is it clear that AZT did not reduce viral replication, or could a reduction have been missed because there is less to measure at that early disease stage, and there were only a few patients in this study arm? It would be a surprise if AZT does not affect viral replication in the lymph nodes in early HIV disease; therefore, we want to see more information before reaching that conclusion.

There has also been some confusion about this study due to the current lack of standardization of terminology. In the Yokohama conference abstract, the authors used the term "HIV burden" to mean the proportion of infected cells. The authors plan to avoid this terminology in the future, because "viral burden" is sometimes used to mean the number of copies of viral RNA in blood plasma; "viral load", "viral activity," "viral reproduction" have also been used, more or less interchangeably, for the latter meaning. No one knows how this usage will standardize in the future; our guess is that "proportion of infected cells" will refer to the former meaning, while either "viral activity" (or perhaps "viral load" or "viral burden") will be used for the latter. The two meanings are quite different, since the proportion of infected cells apparently becomes established early in HIV disease and then tends changes only slowly, while the number of copies of viral RNA in blood plasma can change greatly within days, due to changes in drug treatment or for other reasons. Because of this rapid response, and because the proportion of infected cells is difficult to determine, while tests to measure plasma HIV RNA have now become routinely available (see AIDS Treatment News #204, August 5, 1994), and because HIV RNA level indicates the number of viral particles and correlates with the ability to grow the virus in culture, the plasma RNA level is becoming the measurement of interest for testing new drugs, and for individualizing therapy with existing drugs.

[Note: There was much more information on pathogenesis at the Yokohama conference. We will continue our coverage in future articles.]

References

1. Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K, and Haase AT. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. March 25, 1993; volume 362, number 6418, pages 359-362; comment on pages 292-293.

2. Cohen OJ, Pantaleo G, Graziosi C, Niu M, and Fauci AS. Effect of antiretroviral therapy on HIV burden and replication in lymphoid tissue. Tenth International Conference on AIDS, Yokohama, August 7-12, 1994 [abstract #001B).

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