AIDS Pathogenesis: Recent Articles On Lymph-Node Infection

Lymph-node infection by HIV was in the news last month after
two independent research articles(1,2) and two commentaries(3,4)
were published in Nature, March 25. The findings themselves may
have been overshadowed by emotional reactions which went well
beyond the data.

HIV infection in lymph nodes (which occurs mainly in T-
helper cells and macrophages there) is not news, but was
described in major papers published at least as early as
1986.(5,6) But the earlier papers found evidence of HIV infection
in very few lymph-node cells, with about one in ten thousand or
fewer being infected.(5) Clearly this small number could not
account for the progression of HIV disease by direct cell
killing.

The newly-reported work, using better detection methods,
found much more infection in lymph nodes, although the numbers
varied between research groups and between patients. Embretson
and others(2), who studied four patients, found viral RNA
(evidence of active infection) in three percent to six percent of
lymphocytes and macrophages, depending upon the patient. Viral
DNA was found in 16 to 32 percent of the cells; this could
indicate either active infection, latent infection which could
serve as a viral reservoir and become active later, or defective
virus which might not be dangerous.

Pantaleo and others(1) looked at 12 patients and compared
the proportion of cells infected in the blood and in the lymph
nodes. The numbers varied, but usually the rate of infection was
at least 10 times higher in the lymph nodes than in the blood.
The researchers concluded that "a state of true microbiological
latency does not exist during the course of HIV infection. The
peripheral blood does not accurately reflect the actual state of
HIV disease, particularly early in the clinical course of HIV
infection. In fact, HIV disease is active and progressive even
when there is little evidence of disease activity by readily
measured viral parameters in the peripheral blood, and the
patient is experiencing clinical latency." As a result, standard
tests of blood (which is easy to obtain) missed the more
important infection, which was happening in the lymph nodes.

Anthony Fauci, M. D., director of the U. S. National
Institute of Allergy and Infectious Diseases (NIAID) and chief of
NIAID's Laboratory of Immunoregulation, where much of the work
reported by Pantaleo and others was done, said that this work
"provides a sound rationale for studies of early treatment
strategies, especially with combinations of non-toxic drugs."
Drs. Fauci, Pantaleo, and Graziosi recently published a review of
HIV pathogenesis.(7)

Comment

Some have interpreted the newly published results (which are
no surprise to scientists, having been presented in conferences
during the last year) as implying that antivirals will not work.
The reasoning is that all the approved antivirals, and many of
those now being tested, are reverse-transcriptase (RT)
inhibitors, which only prevent a step in the infection in new
cells, but do not target viral activity in cells already
infected. The newly-published results show that more T-helper
cells than previously known are already infected; therefore, it
is too late for the existing antivirals to help them.

But all of the new results have found no evidence of
infection in a large majority of the susceptible cells;
therefore, it seems that the antivirals still have work to do.
It has long been understood that there are reservoirs of
chronically infected cells which the drugs currently in use do
not inhibit; that is why these treatments only work partially.
But they do help some people; and the recent studies of
"convergent combination therapy" have suggested that combinations
of these drugs might be considerably improved.

What the lymph-node results should do is to focus more
attention on different kinds of treatments, which might work in
chronically infected cells where the RT inhibitors do not. These
approaches include:

* Antivirals to turn off viral activity in infected cells,
for example, tat inhibitors;

* Treatments to kill infected cells, such as compound Q and
others, which are now being tested;

* Other therapies which may reduce viral activity
indirectly, such as pentoxifylline or NAC;

* Therapeutic vaccines of different kinds;

* Other immune modulators, such as thymosin alpha 1 plus
alpha interferon; and

* Various high-tech possibilities, such as antisense and
gene therapy.

One approach to treatment is to attack the virus directly.
Another is to slow the progression of HIV infection, so that the
period of clinical latency could last indefinitely -- or at least
beyond the normal lifespan, or until better treatments become
available. There are many avenues worth exploring.

References

1. Pantaleo G, Graziosi C, Demarest JF and others. HIV
infection is active and progressive in lymphoid tissue during the
clinically latent stage of disease. NATURE. March 25, 1993;
volume 362, pages 355-358.

2. Embretson J, Zupancic M, Ribas JL, and others. Massive
covert infection of helper T lymphocytes and macrophages by HIV
during the incubation period of AIDS. NATURE. March 25, 1993;
volume 362, pages 359-362.

3. Maddox J. Where the AIDS virus hides away. NATURE. March
25, 1993; volume 362, page 287.

4. Temin HM and Bolognesi DP. Where was HIV hiding? NATURE.
March 25, 1993; volume 362, pages 292-293.

5. Harper ME, Marselle LM, Chayt KJ, and others. Detection of
rare cells expressing HTLV-III in primary lymphoid tissue from
infected individuals using a highly sensitive in situ
hybridization method. BIOCHEMICAL AND MOLECULAR EPIDEMIOLOY OF
CANCER. 1986; pages 449-457.

6. Biberfeld P, Chayt KJ, Marselle LM, Biberfeld G, Gallo RC,
and Harper ME. HTLV-III expression in infected lymph nodes and
relevance to pathogenesis of lymphadenopathy. AMERICAN JOURNAL
OF PATHOLOGY. 1986; volume 125, pages 436-442.

7. Pantaleo G, Graziosi C, and Fauci AS. The immunopathogenesis
of human immunodeficiency virus infection. NEW ENGLAND JOURNAL OF
MEDICINE. February 4, 1993; volume 328, number 5, pages 327-335.