Scientists working on the AIDS epidemic have discovered how HIV shuts down the immune cells that would otherwise attack the virus. In test tube studies, they also showed that they are able to reverse the process by blocking the switch called programmed death-1 (PD-1).
The findings were published in two research papers in the current issues of the journals Nature and Nature Medicine.
Prior studies have shown that CD8 positive T cells initially respond to viral infection by reproducing dramatically and producing cytokines that help destroy the viruses, but in chronic infection, high levels of virus appear to overwhelm and exhaust CD8 cells. In one current study, published in Nature, the researchers examined CD8 cells from 71 infected individuals before they began antiviral therapy and found that PD-1 expression was indeed higher on HIV-specific CD8 cells than on cells targeted against better controlled viruses or on CD8 cells from uninfected controls.
HIV-specific CD8 cells with high PD-1 levels were less able to divide and expand in response to HIV proteins. It also became clear that increased PD-1 expression correlated with increased viral load and reduced levels of CD4 helper T cells.
When blood samples from four HIV-positive patients were compared before and after antiretroviral therapy, it was seen that along with the expected drop in viral load response after treatment, there was also a significant decrease in PD-1 expression on HIV-specific CD8 cells. This suggested that elevated PD-1 level may be a response to the high viral loads in untreated individuals.
The researchers were able to reverse the effect of high levels of PD-1 by using antibodies that block the PD-1 pathway. They found that the addition of antibodies to blood cells from infected individuals, leads to the proliferation of HIV-specific CD8 cells in response to viral antigens and production of higher levels of gamma interferon, indicating improved function.
“We wanted to determine whether these T cells had been irreparably damaged or misprogrammed and we found that they are capable of functioning; they’ve just been turned off,” says Dr. Walker, Mass General Hospital, the senior author of the Nature paper.