Blocking a receptor on immune cells that inhibits immune response to viral infections using a specially designed antibody resulted in control of SIV, prolonged survival and impressive anti-SIV immune responses in monkeys - all without antiretroviral therapy - researchers reported this week in Nature.
The receptor, PD-1, is a hallmark of 'exhausted' T-cells, and is found most frequently on the virus-specific T-cells of people suffering chronic viral infections such as cytomegalovirus, hepatitis C and HIV, when the virus-specific T-cells are unable to control viral replication. But up until now it has been unclear whether the high levels of PD-1 expression had any bearing on HIV disease, and whether blocking the PD-1 receptors would have any impact on disease progression.
In a series of animal experiments, researchers from Emory University, Atlanta, along with colleagues at Harvard Medical School, University of Pennsylvania Medical School and the Dana-Farber Cancer Institute, have now shown that blocking the PD-1 receptor offers a potential new pathway both for treating HIV infection - and perhaps for its prevention too.
The investigators tested an antibody for human PD-1 in nine macaques that had been infected with SIV, the simian equivalent of HIV, for varying periods of time. Of the nine animals, five had been infected for three months and four for around 21 months at the time of antibody treatment.
The monkeys received four injections with the antibody over a ten-day period, while five further monkeys received a control vaccination with another antibody.
While four out of five control animals died of simian AIDS within four months, all nine animals that received the PD-1 antibody were still alive and healthy after seven months, and exhibited strong SIV-specific CD8 cell responses, a decline in SIV viral load and an expansion in the number of SIV-specific CD8 cells in both the blood and the gut (the major reservoir of SIV and HIV).
Sustained viral-load declines lasting at least three months were seen in only two of the nine animals (both treated in early infection); in the remainder viral load returned to pre-antibody levels, or began to rebound within 43 days of antibody treatment.
The PD-1 antibody appeared safe during the short period of study, with no observable side-effects and no changes in markers such as liver enzymes, lipids or blood counts after administration. There has been concern that PD-1 antibody, however it is used, could cause autoimmune problems due to an over-stimulation of CD8 cell activity.
PD-1 blockade is being investigated as a treatment for cancer and for hepatitis C; Medarex has two candidates in early clinical trials. According to Nature News, another company hopes to win permission to begin trials of a PD-1 antibody in people with HIV in 2009.
The existing research consortium plans further work with anti-PD-1 in order to test its effects in combination with antiretroviral therapy, as well as the effects of prolonged dosing.
Vijayakumar V et al.Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature (online advance publication, Dec 10 2008). Doi:10.1038/nature07662