Investigators at the Partners AIDS Research Center discovered that a CTLA-4 inhibits the action of HIV-specific CD4 T cells, which should destroy virus-infected cells.
Expression of the CTLA-4 protein was previously known to be elevated on activated T cells. Studies in cancer patients have also shown that the molecule serves to dampen the immune response. Additionally, earlier investigations had suggested a potential role for the protein in HIV infection.
The scientists found that CTLA-4 was overexpressed on the HIV-specific CD4 T cells of infected individuals who had not yet received antiviral treatment. Levels were highest in those with symptoms of acute infection and second highest in chronically infected participants, they say. CTLA-4 expression was lowest among a group of participants whose immune systems were naturally able to suppress HIV replication without antiviral medications.
Elevated CTLA-4 expression also correlated with signs of disease progression, increased viral load, and reduced overall CD4 count, according to the researchers. While antiviral treatment caused viral loads to drop significantly after treatment began, the investigators found 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, report the investigators.
The study will appear in a future issue of Nature Immunology and has already been released online.