T cell turnoff

From Scientific American, December 2007:
HIV is devastating because it attacks and destroys the body’s defense system against pathogens, leaving patients fatally exposed. So what would possess scientists to treat HIV-positive patients with drugs that suppress the immune system?

Such therapy may in fact offer a new approach in the battle against AIDS. An unexpected feature of HIV infection is that in the first few weeks after invasion, the virus hijacks the immune system and sends it into overdrive. Most significantly, the activated T cells—the soldiers that fight germs—not only produce large amounts of cytokines (chemical messengers that help to coordinate a counterattack) but also enter the cell cycle, a process that normally leads to cell division and proliferation. In HIV infection, however, a T cell subtype called the central memory CD4+ T cell appears to enter the cell cycle and undergo apoptosis—cellular suicide—in vast numbers. The activated CD4+ T cell population also helps the virus replicate.

Scientists are not exactly sure how HIV causes the CD4+ T cell population to activate and crash. They do know that the decline is characteristic of HIV infection and use it to make prognoses. They also know that if immune activation is absent, the outlook is very different.
Nowhere is this clearer than in the laboratory with monkeys. The sooty manga­bey, found in West Africa, has somehow adapted to the simian immunodeficiency virus—the nonhuman version of HIV—so that even with a high viral load, it rarely gets sick. In contrast, the Asian rhesus macaque will commonly develop a syndrome resembling AIDS. The difference between these two primates is that the sooty man­gabey experiences only low levels of immune activation, which presumably limits the T cell population crash and viral replication. In contrast, the rhesus macaque’s immune system, like that of humans, is highly activated in the early stages of infection.

This correlation led researchers to wonder what might happen if the human immune system behaved more like the manga­bey’s when confronted by the virus. Experiments have already established that blocking viral replication with antiretroviral medication attenuates immune activation and boosts the number of CD4+ T cells. The next step would be immunosuppressive therapy, which could slow down viral replication by limiting the T cell activation and prevent the CD4+ T cells from committing suicide. “Maybe if we gave antiviral medications and blocked the downstream pathways that are driving T cell turnover, we might be able to enhance CD4+ T cell restoration and T cell function,” says Michael Lederman, director of the Center for AIDS Research at Case Western Reserve University.

Several teams around the world have been investigating this unusual approach, with mixed results. Lederman and his colleagues conducted trials in 2001 and 2003 of the corticosteroid prednisone in conjunction with antiretroviral therapy. The therapy succeeded in blocking immune activation but failed to affect CD4+ T cell populations.

A European team fared better with cyclosporine A. In a nine-patient trial—and later, in a study of nearly 80 patients—CD4+ T cell counts rose to normal levels after eight weeks of cyclosporine A and antiretroviral therapy, says immunologist Giuseppe Pantaleo of the University of Lausanne in Switzerland, a key investigator in the trials. “We were indeed surprised by the magnitude of the effect on the CD4+ T cells,” he remarks.

Pantaleo’s results stand in stark contrast to some previous attempts. In 1989 Canadian researchers attempted to treat patients with AIDS using cyclosporine, with unfortunate consequences. Not only did patients experience severe toxic symptoms from the treatment, but their T cell counts plummeted.

Hence, timing seems to be important with this kind of HIV therapy. “This is not, in my mind, an approach to take during chronic infection, because once infection has been established, the mechanisms of immune activation become much more complicated,” observes Martin Mar­kowitz, staff investigator at the Aaron Diamond AIDS Research Center in New York City. “I don’t think that you want to intervene in a disease that is characterized by progressive immunosuppression with immunosuppression.” Read more.

6 thoughts on “T cell turnoff

  1. It would appear to me that the biggest, if not the only significant, benefit of this approach (if it indeed proves to work) is a vaccine. A vaccine that works opposite to the standard ones, by teaching the T-cells to *not* attack the virus when they meet it, and instead have the virus be killed with other chemical (injected) means upon detection. I would be surprised if this idea hasn’t occurred to someone already, or is not implicit in the article, but it would seem a pity not to explore this avenue!Yiannis Tsiounis, Ph.D.


  2. This form of therapy is not a vaccine, which stimulates or primes the immune system, but rather a treatment that suppresses the immune system.The problem with HIV is that T-cells don’t attack it – the virus has found a way to hijack the T-cell response to enable its own replication and to disable the natural immune response to invasion.Immunosuppression would in theory slow down viral replication and hopefully preserve some natural immune function. It is unlikely to ‘cure’ HIV infection but may at least slow down progression of the disease and reduce the need for such intensive anti-retroviral medication.In terms of vaccines, so far no one has managed to develop a successful vaccine against HIV as it is such an immunologically complex virus and disease that traditional vaccine approaches just don’t work.I hope that answers your question.


  3. This will have interesting application in developing immune based therapy for management of HIV infection.Immune suppression will significantly tone down cytokine expression that is responsible for 1) immune activation against Lymphoid organs,Thymus and subsequent damage 2)Activation of CD4 causing viral replication and apoptosis of infected cd4 cells.After this phase of immune suppression to bring about latency in HIV,immune stimulation will bring up necessary CD4 and CD8 cells and inhibit opportunistic infections.This is going to be the future of HIV management.Can I get some references of published studies regarding your observations of Sooty Mangabey and low levels of immune activation and adapting to SIV.Do they have a normal life expectancy and quality of life(activity) like non infected animalsSunil Bhaskaran Pune India


  4. Hi Sunilthanks for your comments. My information on the sooty mangabey and SIV came from the International AIDS Society conference in Sydney last year, so I’m not sure if or where this data has been published.However you can view the Powerpoint presentation by Dr Jacob Estes, University of Minnesota, from the IAS conference at http://www.ias2007.org/pag/ppt/TUSY404.ppt .I’m afraid I don’t know whether the QOL of infected sooty mangabeys is the same as uninfected individuals, but the data suggests they do not develop AIDS-like symptoms or opportunistic infections. Whether they manifest any other symptoms of SIV infection I don’t know.I believe there will be more data on the immunosuppression approach presented at the upcoming CROI 2008 conference.Bianca


  5. If we accept the premise that we are dealing with an immunosuppressive disease and, as your article in Scientific American points out, we are using an immunosuppressive agent in most cases to “treat” the HIV positive patient, hasn’t this process been used since the first agents(AZT) were used to “treat” HIV positive patients? It appears that the mainstream HIV therapy has gone from most toxic to less toxic chemotherapeutic drugs(protease inhibitors) with the same result. Death.Wouldn’t it make infinitely better sense to have the medical and molecular biological communities seriously study the thousands of HIV + patients who are totally asymptomatic and have not had any of these agents? Wouldn’t that be a great place to start? John Burgin, DDS


  6. Hi BiancaThank you for this link.Sooty Mangabey SIV response1)The immune response to early viremia directed towards the lymphatic organs where high viremia occurs through macrophages,is for a limited period.As a result,the damage inflicted to lymphatic tissue by way of fibrosis is minimal.The overall health of the immune organs like lymph system and thymus where progenitor immune cells mature and differentiate is very important for preservation of immunecompetency.2)After the initial viremia and high limited period immune response,the subsequent immune response is not intense.Perhaps,there may not be a situation of high proinflammatory immune status as seen HIV in humans.This perhaps explains slow replication( or latency of the virus in sooty mangabey).Some kind of a homeostasis is achieved with viral set point and immune health with respect to cd4 counts.3)Perhaps,this can be explained by a process of effective immune regulation that happens in sooty mangabey.Foxp3 protein and cd25 subset of cd4 cells will be involved in this regulation.Progressive immune deficiency in HIV is composite effect of CTL death(apoptosis and necrosis)and irreversible damage caused to immune organs by frequent immune activations.This also explains cytopenia in AIDS patients.Immune regulatory strategies will mimic sooty mangabey response to sivinfection.This is going be the holy grail in HIVJohns suggestion to study non-progressors is very relevant.May be many of them have an innate immune regulation maintaining homeostasis and good health.Perhaps drugs directed towards “HIV harm reduction” will prolong the life of non progressors by not letting them progress to opportunistic infections and aids!Sunil Bhaskaran


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