From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: More on Th1/Th2
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6443
Organization: unspecified
Date: Wed, 11 Nov 92 09:38:58 PST

This article was published in the 11/92 issue of the PWA Newsline which 
is the publication of the People With AIDS Coalition. PWA encourages 
dissemination of AIDS information.
************************************************************************
SERONEGATIVES WITH H.I.V.

by Marcus Boon

   As is well known by now, the big news from the Amsterdam conference 
was the discovery of AIDS cases in people apparently without HIV 
infection. Less well know, but of equal interest, was the discovery of 
people who have apparently been infected by HIV, but have no trace of 
the virus, or antibody to it, in their body. In other words, these are 
healthy seronegative, HIV infected people. Although this is the kind of 
news that is likely to flip out healthy "at risk" seronegatives like 
myself, it's actually pretty good news for everyone involved.

   No virus successfully infects everyone it comes into contact with. 
Depending on the specific circumstances, a percentage of people will get 
rid of the virus, or suppress it to the point where it becomes 
undetectable. It has been know for a long time that there are people who 
have been exposed to HIV, through unprotected sex, or sharing needles 
with someone who is HIV seropositive, who have not developed antibodies 
to HIV.

   A few years ago, Gene Shearer and his co-worker Mario Clerici of the 
National Cancer Institute began studying such people, and discovered 
that, although they could find neither antibody to HIV, nor trace of the 
virus using the sensitive PCR assay, many of the high risk seronegatives 
they studied did respond to synthetic HIV proteins in a way that 
indicated that they had encountered the virus before (1). Specifically, 
it appears that these high-risk seronegatives were producing a cell-    
mediated immune response, in the form of killer T cells, which was 
apparently able to successfully clear the body of virus.

   Shearer and Clerici are continuing their studies, and seem to be 
finding that the majority of high-risk seronegatives produce this 
particular immune response. Fred Valentine at New York University is 
finding similar results. Three is some question as to whether the PCR 
test being used really demonstrates that the people in the study have 
been exposed to HIV--although most scientists believe it does. 
Additionally, a number of low risk seronegatives (5 percent), who seems 
less likely to have been exposed to HIV, also produce the same reaction 
to the synthetic HIV proteins.

   What this all means is that there is apparently such a thing as a 
successful immune response to HIV, and that this response involves 
cell-mediated as opposed to humoral (or antibody producing) immunity. 
Perhaps this shouldn't come as a surprise. AIDS is primarily caused by a 
defect in cell-mediated immunity. Most of the opportunistic infections 
(OIs) seen in AIDS are intracellular organisms--parasites, fungi, 
viruses, or mycobacteria that live in cells. They cause OIs because the 
arm of the immune system responsible for keeping them in check isn't 
working. In other words, cells responsible for attaching and destroying 
infected cells, like macrophages, killer T cells, and natural killer 
cells aren't doing their job. The other part of the immune system, 
antibody-producing B cells, is hyperactive, producing too many 
antibodies, often without specificity for the things that they're trying 
to destroy. One of the big puzzles about AIDS has been the fact that, on 
the one hand, people with AIDS have an immune deficiency, while on the 
other hand they seem to have immune hyperactivity. Shearer and Clerici 
have a very elegant explanation for this paradox (2).

   Studies of mice have revealed that T4 or T helper cells appear to 
control the immune response by producing two distinct patterns of 
chemical messengers, or cytokines (3). TH1 cells produce cytokines like 
interleukin 2 and gamma interferon, which are responsible for cell-    
mediated immune function. TH2 cells produce cytokine like interleukin 4, 
6, and 10, which stimulate B cells to produce antibodies. It's unknown 
whether TH1 and 2 cells are actually different kinds of T4 cells, or 
whether they represent different phases of the same cell--but it has 
been shown recently that humans appear to have the same setup as mice 
(4).  The body generally only produces one of these responses--and when 
TH1 cells are stimulated, they seem to shut down the TH2 cells and vice 
versa. Shearer and Clerici suggest that AIDS, with its overactivation of 
B cells, involves an extended TH2 response which eventually shuts down 
the TH1 response and that the high-risk seronegatives they have studied 
are apparently able to contain HIV using the TH1 response. According to 
their hypothesis, being HIV seropositive is already suggestive of a 
shift toward a TH2 response--a response that may not be able to suppress 
HIV, or other intracellular organisms. Studies of certain parasitic 
diseases, and preliminary work on retrovirally-induced mouse immune 
deficiency syndrome (MAIDS) also show a correlation between a chronic 
Th2 response and disease (5). Additionally, whey your are allergic to 
something, you experience a strong TH2 response.

   Recent studies suggest that T8 cells may produce TH1 and TH2-like 
cytokine profiles which an regulate the activities of the immune system. 
It has even been suggested that the difference between T4 and T8 cells 
responsible for 'type 1' and 'type 2' responses (6). This seems 
unlikely. It should be remembered that T4 and T8 cells themselves were 
discovered only ten years ago, and there is no guarantee that they 
represent the final word on the subject.

   Preliminary studies of HIV seropositive people by Shearer and Clerici 
show a complex set of relationships between the production of various 
cytokines by T helper cells and the healthiness of the immune system. 
People with the most intact immune responses maintain a TH1 response, 
although a weaker one than seronegatives. Progressive weakness of the 
immune system is marked first by a dominant TH2 response, and later by a 
weakness of both TH1 and TH2 response.

   This work is still at an early stage. Some observations about AIDS 
appear to contradict the idea that the shift from a TH1 to a TH2 
response help cause AIDS. For instance, high anti-HIV antibody levels 
are considered an indicator of an effective immune response. High gamma 
interferon levels, which should indicate a TH1 response, are often 
observed in people with AIDS. Not enough is known about the levels of 
many of the other cytokines involved. As always, the temptation to 
construct a model of AIDS that explains everything, without having the 
necessary information, is there. But in the broad sense, this model does 
seem to have a lot going for it.

   Jonas Salk, the famed creator of the polio vaccine, has given his 
support to Shearer and Clerici's ideas. Present work on vaccines is 
almost entirely given over to stimulating antibody (i.e., a TH2 
response) in people. But if stimulating antibody production is part of 
the disease process, then this could be disastrous. It must be said that 
results from vaccine studies done so far have not been disastrous. But 
time will tell. Salk is working on a vaccine stimulates a TH1 response, 
both in HIV infected and uninfected people.

   Shearer and Clerici's work provides an intriguing explanation for the 
levels of HIV infection found in Africa. Since parasitic infection, 
which is rampant in Africa, is a strong TH2 inducer, parasites could as 
a co-factor which would account for the apparently high level of HIV 
seropositivity in Africa. This suggests that it is a very good idea for 
all HIV seropositives, or those "at risk," to get themselves checked out 
for amoebas, Giardia and so on--and get treated if necessary.

   Other therapeutic strategies that correlate with Shearer and 
Clerici's work involved modulating cytokine production, or producing 
more general shifts from humoral to cell-mediated immunity. DHEA 
stimulated IL-2 production in mice. Chloroquine is an IL-6 inhibitor. 
DNCB appears to augment cell-mediated immunity. Community Research 
Initiative on AIDS in New York City is developing a study of very low 
does oral cyclophosphamide, which is known to suppress antibody 
production and augment killer T cells and delayed hypersensitivity. 

[bg. according to The Pharmacological Basis of Therapeutics, page 1265, 
cyclophosphamide interferes with the proliferation/differentiation of 
both B cells and T8 cytotoxic cells.]. 

No doubt other agents that could be of use exist--but who will study 
them? If Shearer and Clerici's observations in high-risk seronegatives 
prove to be correct, then a detailed understanding of what makes such 
individuals immune response successful should be of enormous value in 
developing new ways of combating AIDS.

  It is not clear what cause the shift of the immune system from a 
healthy response to an unhealthy one, or indeed, what makes some people 
who come into contact with HIV seroconvert while others remain 
seronegative. Is it HIV itself, or something else? Joe Sonnabend, MD, 
CRIA's medical director, has long suggested that HIV infection and 
seroconversion are entirely separate event with their own risk factors, 
and that antibodies to HIV, or indeed the detectable presence of HIV 
itself, could be merely a marker of an as-yet-unknown defect in the 
immune system.

   Finally, it should come as a relief to know that immunologists of the 
quality of Shearer and Clerici are working on AIDS. Shearer has been 
working rather discreetly but steadily on AIDS since the beginning of 
the epidemic, and his work is in marked contrast to that of many of our 
most prominent scientists. Unlike Anthony Fauci, whose lab seems to 
operate by having a finger in every pie (including Shearer's, 
thankfully), Shearer has worked methodically to try to understand the 
issues, ask the right questions, and to integrate seemingly 
contradictory observations in a plausible manner. He is the kind of 
researcher that might actually manage to solve some of the mysteries of 
AIDS.

REFERENCES

   1. Clerici, M. et al. Cell mediated immune response to Human 
Immunodeficiency Virus (HIV) Type 1 in seronegative homosexual men with 
recent sexual exposure to HIV-1. J Infect Dis 165, 1012-19, 1992.

   2. Shearer, G.M., Clerici, M. T helper cell immune dysfunction in 
asymptomatic HIV-1 seropositive individuals: The role of Th1-Th2 cross 
regulation. Prog Chem Immunol 1992, in press.

   3. Mosmann, T.R. et al. Diversity of cytokine synthesis and function 
of mouse CD4+ T cells. Immunol Rev, 123, 209-29, 1991.

   4. Romagnani, S. Type 1 T helper and type 2 T helper cells: 
Functions, regulation and role in protection and disease. Int J Clin Lab 
Res 21, 152-8, 1991.

   5. Sher, A. et al. Role of T cell derived cytokines in the 
downregulation of immune responses in parasitic and retroviral 
infection. Immunol Rev 127, 183-204, 1992.

   6. Bloom, B.R. et al. Revisiting and Revising Suppressor T cells, 
Immunol Today 13, 131-135, 1992.
Newsgroups: sci.med.aids