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HAART Reduces Inflammation in the Blood But ...

February 2009

HAART generally reduces the production of HIV, allowing the immune system to begin repairing itself. As a result, the number of important CD4+ T-cells in the blood increases and these and other cells of the immune system regain their ability to detect and fight infections. However, HAART does not cure HIV infection and the immune system's repair is partial.


Red Alert

In HIV infection, it appears that the immune system becomes activated shortly after the virus has entered and begins to spread throughout the body. In the case of most germs, this activation and subsequent inflammation is useful because it helps alert and marshal the immune response to control an infection. But in the case of HIV, this activation may not be helpful because the virus appears to take advantage of activation in order to help it infect more cells and to turn the immune system against itself.


Location Is Everything

Only 2% of the immune system's cells are in the blood. The majority of these cells are in lymph nodes and tissues. And most of the lymph nodes and tissues are found around the intestines. Since HIV infects cells of the immune system, most HIV is also found where those cells are, in lymph nodes and tissues. Lymph nodes and tissues are bustling hives of activity as the immune system battles germs. Historically, much HIV research has been done only on the cells of the immune system that can be found in the blood.


Back to the Lymph Nodes

In the late 1970s, when a small number of people with AIDS sought help, researchers studying the immune systems of these mysteriously ill patients noticed that they had persistently swollen lymph nodes. Biopsy and examination of the lymph nodes in those days also revealed inflammation and, in some cases, tumours.

Now researchers are once again revisiting the lymph nodes to find out what's going on there. Researchers from the United States' National Institutes of Health (NIH) and Sweden's Karolinska Institute are collaborating on obtaining a better understanding of how HIV damages the immune system, looking at lymph nodes in people infected with HIV and monkeys infected with the AIDS-causing virus SIV. Their findings reveal "an underlying immunologic condition" that may prevent the complete recovery of the immune system, even in HAART users.

The NIH-Karolinska's findings may also help other scientists to gain a better grasp of how HIV damages the immune system and to find ways to prevent and reverse this damage.


Study Details

The research team collected blood samples from the following volunteers:

Doctors removed tonsils from the following volunteers:

Blood and lymphatic tissue were taken from five SIV positive monkeys before and after they received anti-HIV therapy.


Results -- Blood

HIV positive people who were not taking HAART had high levels of certain proteins, called TRAIL and FasL, that can cause cells of the immune system to commit suicide. In cells, this process of self-death triggered by those proteins is called apoptosis. In contrast, HAART users had near normal levels of the death-inducing proteins TRAIL and FasL.


Death's Friends

In order for TRAIL and FasL to work (cause apoptosis), they have to find their corresponding receptors on a cell and bind to those receptors. In the case of TRAIL, its receptor is called DR5 (death receptor 5) and FasL's receptor is called Fas.

In general, CD4+ cells in the blood of people not using HAART had high levels of these two receptors.


Results -- in the Lymph Tissues (Tonsils)

Levels of TRAIL and FasL that can trigger cell suicide were elevated in the lymph tissue of HIV positive people who were not taking HAART. The same was true for the death receptors DR5 and Fas in people not taking HAART.

However, in the lymph nodes and tissues of HAART users researchers were surprised to find that levels of death receptors -- DR5 and Fas -- were at least twice as high as in HIV negative people. Their surprise occurred because in the blood of HAART users, levels of these receptors were near normal.

Stunned by these findings, the research team duplicated its work in SIV positive monkeys. They obtained the same results.


A Note on HIV

During HIV infection, the virus spreads to lymph nodes and tissues, where it infects and directly kills cells of the immune system. However, HIV can indirectly cause death and immunologic mayhem. It can hyper-activate the immune system, making it more susceptible to damage, and it can turn the immune system on itself, causing T- and other cells to unnecessarily undergo self-destruction, or apoptosis.

A hyper-activated immune system, despite the use of HAART, in which CD4+ cells have excessive levels of death receptors, is susceptible to further damage by invading germs. For instance, coinfection with members of the herpes virus family (HSV-1, HSV-2, CMV, EBV, HHV-8 and so on), hepatitis C virus and syphilis germs could result in increased levels of the death proteins TRAIL and FasL. Since many immune cells in a hyper-activated immune system are already primed for death by displaying DR5 and Fas, exposure to TRAIL and FasL because of co-infection could further weaken the immune system.

The findings from the Swedish-American team may help to explain why the immune system is only partially repaired despite years of HAART. Now further research needs to be done to find out why, even with the use of HAART, CD4+ cells are so ready to die.


References

  1. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: cause and consequences. Journal of Pathology. 2008 Jan;214(2):231-41.
  2. Grossman Z, Meier-Schellersheim M, Paul WE, et al. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nature Medicine. 2006 Mar;12(3):289-95.
  3. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Medicine. 2008 Oct 21;5(10):e203.
  4. CadoganM, Dalgleish AG. HIV immunopathogenesis and strategies for intervention. Lancet Infect Diseases. 2008 Nov;8(11):675-84.
  5. Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virusinfected macaques. AIDS. 2009 Jan 2;23(1):35-40.
  6. Boasso A, Hardy AW, Anderson SA, et al. HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation. PLoS One. 2008 Aug 13;3(8):e2961.

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