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Exhaustion of HIV-specific T cells may be caused by chronic exposure to virus

May 06, 2008

Better understanding of immune response to virus required for vaccine development

The "exhaustion" of immune cells that target HIV appears to result from chronic exposure to the virus, specifically exposure to the particular protein segments targeted by the pathogen-killing HIV-specific CD8 T cells. A study from researchers at the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH), appearing in the May issue of the open-access journal PLoS Medicine, may have answered a key question regarding the immune response to HIV infection: is the functional impairment of HIV-specific cytotoxic T lymphocytes (CTLs) the cause or the result of unchecked viral replication in chronic progressive HIV-1 infection"

"Although we know that CTLs can control replication of HIV, we still don't know which particular features of the CTL response are key to this control," says Hendrik Streeck, MD, of PARC-MGH, the paper's lead author. "Better understanding how the quality of the T-cell response changes during HIV infection will be necessary for the design of effective T-cell-based vaccines against HIV."

Previous research has shown that, in most HIV-infected individuals, HIV-specific CTLs gradually lose their ability to proliferate and secrete the cell-killing substances called cytokines as infection proceeds. In parallel, the immune system's ability to control viral replication diminishes over time. It was not clear, however, whether the exhaustion of HIV-specific CTLs was caused by or resulted from persistent viral replication. The PARC-MGH team study was designed to address that very issue.

The study enrolled 18 participants who had recently become infected with HIV. Antiviral treatment was started in 7 participants, while 11 remained untreated during the study period. During the following months, the researchers monitored participants' viral loads and also analyzed the ability of their CTLs to respond to the specific viral protein segments against which the cells were targeted. In participants who received antiviral treatment, viral loads quickly dropped to undetectable levels, and HIV-specific CTLs maintained or even improved their response against their target proteins during the four month after study enrollment.

Viral loads in untreated participants gradually rose during the eight months after enrollment, and during that time HIV-specific CTLs gradually lost functional capacity. To further investigate the interaction between CTLs and their target viral peptides, researchers examined what happened when target peptides mutated and were no longer recognized by the T cells. In that situation, CTLs specific for the original version of the mutated peptides regained their functional capacity, but CTLs targeted against unchanged peptides continued in an exhausted state. These results support the theory that it is persistent contact with the peptide antigen that leads to CTL exhaustion.

"To understand what's happening in any battle, you need to know what's going on with the soldiers as well as with the enemy, so investigating the nature of CTL responses in HIV infection requires monitoring both virus and host responses simultaneously," Streeck says. "Therefore, it is important that HIV vaccine trials evaluate the immune responses carefully in the context of the virus, as the virus might already have evolved. The inability of the vaccine-induced immune response to cross-recognize the infecting virus might actually have contributed to the failure of recent HIV vaccine trials." Streeck is a research fellow in Medicine at Harvard Medical School.

Massachusetts General Hospital