HIV hyperactivates, not suppresses, the immune system

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http://www.the-scientist.com/yr2003/jun/research1_030603.html

 

Studying SIV to Understand HIVHIV hyperactivates, not suppresses, the immune

system, causing CD4+T-cell depletion | By Myrna E. Watanabe

Courtesy of Frank Kiernan

PICTURE OF HEALTH? This 15-year-old mangabey at the Yerkes National Primate

Research Center in Atlanta has been SIV-infected for at least 10 years.

 

In the past, physicians who treated AIDS patients understood that this deadly

disease was one of immune deficiency. Their patients were immunosuppressed,

subject to opportunistic infections, and had odd cancers. Today, because of

continuing research on the human and primate immune systems and their responses

to retroviruses, AIDS researchers realize that the immunosuppression associated

with AIDS is a result of chronic immune hyperactivation. Evidence for this comes

from research on a primate called sooty mangabeys, which lives in equatorial

Africa.

Sooty mangabeys normally contract simian immunodeficiency virus (SIV) through

sexual contact. Despite evidence that SIV has direct toxic effects on CD4+ T

cells, the monkey's immune system remains intact, as lost cells are replaced

with new ones. This finding, published by Mark Feinberg and colleagues at Emory

University School of Medicine,1 may be the clincher in a developing hypothesis:

Virus-mediated, direct T-cell killing is not sufficient to cause AIDS; rather,

chronic immune activation may eventually result in immune suppression. But the

fundamental questions remain unanswered: Why does the mangabey's immune system

prevail, despite SIV infection, while human immune systems overreact to HIV?

What causes T-cell depletion in these immunodeficiency diseases?

" I think the basic message is that AIDS is not simply a function of the virus.

It is ... [also] how the immune system responds to the virus, " says Feinberg.

" The immune system, while it's chasing the virus, may inadvertently be a major

driving force [in disease progression]. AIDS is the cumulative effects of the

direct consequences of the virus and all the consequences that derive from a

maladaptive response to the virus. " Mangabeys, which naturally harbor and

transmit SIV, don't have these maladaptive responses, he says.

Feinberg's work is drawing praise from his peers, because, among other issues,

he says it shows that primate species can evolve to tolerate HIV-like infection.

" This is, of course, a lovely piece [of research], " says Frank Miedema, research

director at the Sanquin Blood Supply Foundation in Amsterdam, Netherlands.

HOW SOOTY MANGABEYS COPE During their first two years or so, mangabeys are

virus-negative, but as they become sexually active, they become infected and

produce antibodies to SIV. Like many other primate species, mangabeys exhibit no

AIDS-like symptoms, even in the face of high viral loads.

Feinberg and colleagues found that, although SIV does have direct toxic effects

on CD4+ T cells, these effects are insufficient to cause AIDS. He ponders: " Do

the mangabeys have any impairment of the immune regenerative compartments? No.

Do they have a predisposition for uninfected cells to undergo apoptosis? The

answer is also no. " Mangabeys may be losing CD4+ T cells directly from viral

infection, but they have no problem replacing those lost cells. The mangabey's

naïve T-cell compartment, Feinberg says, is preserved and intact, unlike

infected humans, in which naïve T cells are progressively devastated.

RELEVANCE TO AIDS " In HIV disease, the virus comes in, there's clearly

infection, there's clearly immune activation against the virus. What happens

after that is a compensatory series of responses to deal with the change in the

equilibrium, " wrote Joseph McCune of the Gladstone Institute of Virology and

Immunology, University of California, San Francisco, in a review of the role of

CD4+ T cells.2 In an interview with The Scientist, McCune says that the

pertinent question is: How, after individuals get the virus, does the disease

progress? After initial HIV infection, the virus concentrates at the lymph

nodes, causing T cells to migrate to the nodes and proliferate. As HIV becomes

activated in the CD4+ T cells, the virus destroys them by apoptosis. McCune

posits that cell loss activates a sensing mechanism, generating " positive

regulatory signals " to increase T-cell production.2

In a typical viral infection, the increased number of T cells eventually gets

the invading pathogen under control. But in HIV infection, the newly produced T

cells serve as HIV targets, which leads to more T-cell production. " Almost

certainly, in an acute [HIV] infection you get a lot of destruction of CD4+

cells directly as a result of the virus, " says Daniel Douek, chief, human

immunology section, Vaccine Research Center at the National Institutes of

Health. " Enter into the chronic phase and that phase is hallmarked by high

levels of immune activation, which the virus causes somehow. " This combination

of virus and highly activated immune system is deadly, Douek says, " because the

virus, by far, prefers to infect and replicate in activated CD4+ T cells. Even

more important than direct destruction of T cells by HIV may be the general

chaos caused by the infection. For example, Feinberg, argues that indirect

mechanisms may be prominent or even primary in T cell loss. "

Miedema notes that " HIV is driving the [T-cell] division, and also that naïve T

cells are being recruited. " Naïve T cells are those that have matured through

the thymus, but have not yet been exposed to any antigens. The role that the

thymus plays in naive T-cell production is one matter of contention. " The thymus

cannot put more [naïve] cells out because the thymus is just really a dead organ

in adults, " Miedema says. But McCune awards a small role to the thymus, at least

in young adults. Miedema, willing to concede that these are gray areas, says

that the endgame in HIV infection results from an eventual lack of naïve T

cells: " If your naïve cells are being recruited year in and year out, that will

be the problem. "

Another complication: HIV mutates readily. " [HIV] tends to be able to mutate

into new antigens, " says McCune. This, adds Feinberg, can allow the virus to

escape from immune pressure. In HIV infection activated T cells show numerous

dysfunctions: " They can make cytokine but cannot proliferate; [they] can

recognize antigen but can't kill, " McCune explains. Douek notes that " Although

the HIV- specific T-cell response can effectively suppress viral load, we cannot

really, with our hands on our hearts, say that control of disease progression

depends on a high- frequency response. " Long-term nonprogressors (people who are

HIV-positive but who show no signs of disease for many years) " don't necessarily

have stronger [immune] responses than rapid progressors. "

PRIMATE RESISTANCE Beatrice Hahn, University of Alabama at Birmingham, says that

data on natural SIV infection exist on about 32 species of nonhuman primates.

" With the exception of the chimpanzees, these primates seem to be infected at

high prevalences through their natural habitat, " and these prevalences seem to

increase with age, she says. The prevalence in infants is usually 0%, whereas

the prevalence in multiparous females may be more than 90%. Yet these animals,

like Feinberg's mangabeys, are SIV-tolerant. " We believe the other

[nonchimpanzee] primate species have been infected for a long time, " says Hahn,

" maybe millions of years. "

Natural host species for SIV infection, says Feinberg, appear to share the same

biology. " These animals have high viremia and no disease, which would suggest

that the choice that has been made in evolution [is to] tolerate the viremia. "

Feinberg notes a parallel to the human response to HIV: " For some reason,

different people have either more or less immune activation following infection

with HIV, " which he relates to incompletely defined genetic factors of the host.

Hahn points out that HIV may be much more similar to SIV infection in

chimpanzees, which rarely are naturally infected. She believes that about 10,000

years ago, chimpanzees may have been infected through hunting and eating other

SIV-infected primates. Hahn and colleagues have hypothesized that because of the

genetic similarity between HIV-1 and chimpanzee SIV, HIV-1 jumped from

chimpanzees into humans.3 Says Hahn, " I can tell you that the primates are chock

full of SIV and I can also tell you that humans are hunting primates all over

the place and are exposed and have been exposed [to SIV]. " The adaptations of

the chimpanzee immune system to SIV, notes Hahn, could well mirror what will

occur in humans. Says Feinberg: " We may find that people have the response

that's similar to the mangabeys. "

Myrna E. Watanabe is a freelance writer in Patterson, NY.

References

1. G. Silvestri et al., " Nonpathogenic SIV infection of sooty mangabeys is

characterized by limited bystander immunopathology despite chronic high-level

viremia, " Immunity, 18:441-52, March 2003.

 

2. J.M. McCune, " The dynamics of CD4+ T-cell depletion in HIV disease, " Nature,

410:974-9, 2001.

 

3. M.L. Santiago et al., " SIVcpz in wild chimpanzees, " Science, 295:465, 2002.

 

 

 

IMMUNE MODULATION COMING FULL CYCLE

In 1993, Ellen Vitetta coauthored a paper on using an immunotoxin to destroy

activated T cells, plus the immunosuppressant drug cyclosporine to inhibit

quiescent T cells from producing HIV.1 Vitetta, director of the Cancer

Immunobiology Center, University of Texas Southwestern Medical Center, Dallas,

recalls that the idea of inhibiting HIV replication through

immunosuppression--on a disease characterized by immunosuppression--was

considered to be " totally idiotic. "

 

But, everything recycles. With newfound knowledge that AIDS results from immune

hyperstimulation, she says that immunosuppression " could take a good

revisiting. " A number of immunosuppressants or immunomodulators against HIV are

in early stages of study.

 

Robert Wallis, University of Medicine and Dentistry, New Jersey Medical School

in Newark, and his colleagues are treating patients who have both tuberculosis

(TB) and AIDS with the immune modulator drug etanercept (Enbrel), which

specifically inhibits tumor necrosis factor (TNF). In HIV infection, there is

" sort of a progression toward AIDS, this chronic stimulation and chronic loss of

cells due to apoptosis, " Wallis says. In patients with TB, " It seems the

progression to AIDS is more rapid. " The hypothesis: TNF immune activation is

related to apoptosis. Inhibit TNF, and apoptosis should not occur.

 

Patrick Haslett, University of Miami, and colleagues are studying the effects of

the immune modulator thalidomide. In vitro, in the presence of antigenic

stimulation, such as HIV or cytomegalovirus, thalidomide costimulates CD8+ and

CD4+ T cells, says Haslett. The researchers will test whether thalidomide is

costimulating antigen-specific T-cell responses. " I think the effect of the drug

is a lot more subtle than immunosuppression, " he says. Previously used as an

anti-inflammatory agent, thalidomide may be an immune activator. If they find

that the drug stimulates antigen-specific immune responses, they plan to test

thalidomide analogs that have a better safety profile than the original drug.

 

Vitetta's team is testing the effects of the immunotoxin ricin, linked to

monoclonal antibodies, specific for classes of CD4+ T cells, latently infected

with HIV.2

--Myrna E. Watanabe

 

 

References

1. K.D. Bell et al. " Combined used of an immunotoxin and cyclosporine to prevent

both activated and quiescent peripheral blood T cells from producing type 1

human immunodeficiency virus, " Proc Natl Acad Sci, 90:1411-5, February 1993.

 

2. J. Saavedra-Lozano et al., " An anti-CD45RO immunotoxin kills latently

infected human immunodeficiency virus (HIV) CD4 T cells in the blood of

HIV-positive persons, " J Infect Dis, 185:306-14, 2002.

 

 

 

 

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