London, Oct 1 : Researchers have discovered a regulatory protein, called CTLA-4, which they believe is a second molecular “switch” responsible for turning off the immune system’s response against HIV.

The study in which the protein was discovered was conducted by researchers at the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH) led by Dr Bruce Walker.

Last year members of the same team identified a molecule called PD-1 that suppresses the activity of HIV-specific CD8 T cells that should destroy virus-infected cells.

They have now found that CTLA-4 inhibits the action of HIV- specific CD4 T cells that control the overall response against the virus.

“We’ve shown that a known regulator of the immune system, CTLA-4, is present in elevated levels on the virus-specific CD4 cells that should be managing the body’s response against HIV,” Nature Immunology quoted Daniel Kaufmann, MD, of PARC and the MGH Infectious Disease Unit, a co-first author of the study, as saying.

CTLA-4 protein is known to be present in elevated levels on activated T cells, those that have encountered a pathogen and are multiplying rapidly to mount an immune response.

“We also found that CTLA-4 expression rises as HIV infection progresses and that the molecule switches off CD4 cell function in a way that appears to be reversible,” Kaufmann added.

As a part of the study the researchers examined how CTLA-4 inhibits the action of HIV-specific CD4 T cells that leads to the immune-system breakdown of AIDS.

The authors first found that CTLA-4 was over expressed on the HIV-specific CD4 T cells of infected individuals who had not yet received antiviral treatment.

CTLA-4 levels were highest in those with symptoms of acute infection and second highest in chronically infected participants.

The levels were lowest among a group of participants whose immune systems were naturally able to suppress HIV replication without antiviral medications – “elite controllers” in whom viral levels are too low to be detected.

The elevated level also correlated with signs of disease progression – increased viral load and reduced overall CD4 count. While antiviral treatment caused viral loads to drop significantly after treatment began, it resulted in only modest and slow drops in CTLA-4 expression.

In vitro tests of the effects of blocking the CTLA-4 molecule improved the function of HIV-specific CD4 cells. Comparing the effects of blocking CTLA-4 with those of blocking PD-1 or both molecules produced functional improvements that varied considerably between participants, signifying a complex relationship between the pathways controlled by the two molecules.

“Both of these pathways contribute to dysfunction of HIV-specific T cells and both may be considered targets for therapeutic intervention. But since their mechanisms are so complicated, further study is needed before clinical trials can be planned,” Kaufmann, an instructor in Medicine at Harvard Medical School (HMS), said.

”Understanding why the immune system fails to control HIV is essential for development of vaccines and new therapies,” Walker said.

“These studies suggest that the immune system is turning itself off prematurely in HIV-infected persons, and the big challenge now is to figure out if we can turn it back on, getting it to do what it is supposed to do, without causing collateral damage in the process,” he added. (With inputs from ANI)