One of the primary mysteries of the AIDS epidemic – why the immune system is unable to control HIV infection – may have been solved by an international research collaborative. In an upcoming issue of Nature, the team reports how a molecular pathway involved in the immune cell "exhaustion" that characterizes several other chronic viral infections plays a similar role in HIV infection.
They also found that blocking the pathway restores some function to HIV-specific CD8 and CD4 T cells. The paper from researchers at the Partners AIDS Research Center at Massachusetts General Hospital (MGH), the University of KwaZulu-Natal (UKZN) in South Africa, and other institutions has received early online publication.
"Back in 1987 our MGH team confirmed the existence of HIV-specific CD8 cells, the cytotoxic T lymphoctyes that should destroy virus-infected cells," says Bruce Walker, MD, director of the Partners AIDS Research Center (PARC) and principal investigator of the Nature study. "But it didn't make sense that these cells were found in high numbers in persons with late-stage disease (AIDS), indicating that they were somehow not doing their job. These new findings finally make sense out of our early discoveries and subsequent findings by others in the field: The immune cells are there, but they have been turned off in persons with high viral loads."
Several recent studies have shown that a molecular pathway involving a receptor called PD-1 (Programmed Death-1) inhibits the immune system in chronic viral infections – those in which the immune system does not completely clear the virus. CD8 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. Recent studies in mice by Rafi Ahmed, PhD, of Emory University School of Medicine and Gordon Freeman, PhD, of Dana-Farber Cancer Institute – both co-authors of the current report – indicated that PD-1 is overexpressed on these exhausted cells and may act as a molecular switch to turn off their activity.
For the current study, designed to find whether a similar process takes place in HIV infection, the US-based researchers worked closely with collaborators from Durban, South Africa, an area where more than 30 percent of the population is HIV-infected. They first examined HIV-specific CD8 cells from 71 infected individuals who had not yet begun antiviral therapy and found that PD-1 expression was indeed higher on HIV-specific cells than on cells targeted against better controlled viruses or on CD8 cells from uninfected individuals. HIV-specific cells with high PD-1 expression also were less able to divide and expand in response to HIV proteins. Relating PD-1 levels to key markers of HIV disease progression in the African study participants turned up significant associations: increased PD-1 expression correlated with increased viral load and reduced levels of CD4 helper T cells.
To examine whether antiviral therapy might change the expression of PD-1, the researchers examined blood samples taken from four HIV-positive participants before and after they began antiretroviral therapy. Along with the expected drop in viral load in response to treatment, there was also a significant decrease in PD-1 expression on HIV-specific CD8 cells, suggesting that elevated receptor expression may be a response to the high viral loads of untreated individuals.
Using antibodies to block the PD-1 pathway in blood cells from infected individuals significantly increased the ability of HIV-specific CD8 cells to proliferate in response to viral antigens and also increased the cells' production of the cytokine gamma interferon, indicating improved function. Blocking the PD-1 pathway also increased the proliferation of HIV-specific CD4 cells, and even cells from individuals that previously had no detectable response had robust proliferation after pathway blockade, indicated that cells that had been turned off could be turned back on.
"It has been thought that the ineffectiveness of HIV-specific T cells resulted from progressive, irreversible damage or bad cellular 'programming'," explains Daniel Kaufmann, MD, of PARC and the MGH Infectious Disease Unit, a co-first author of the Nature paper. "While this might still be partially the case, our finding that defects in important functions of exhausted T cells can be reversed demonstrates that active inhibitory mechanisms may play a major role in blocking T cell function. In other words, the cells may be turned off but not permanently disabled."
Co-first author Cheryl L. Day, PhD, agrees. "Natural regulatory systems that help control the immune system appear to be shutting it down before its work is done. One of the next questions we need to answer is whether we can turn it back on for HIV-infected patients in a way that will benefit them without incurring serious side effects." Day is associated with the Doris Duke Medical Research Institute at UKZN and the Partners AIDS Research Center.
"We could not have accomplished this work without our collaborators in South Africa," says Walker. "We began our project there believing we might find clues that could only be uncovered at the heart of the epidemic, and this study bears that out. The ability to conduct studies with large numbers of untreated people – who are now receiving treatment at clinics we helped to establish – allowed us to find the link between PD-1 expression and viral load." Walker is a professor of Medicine at Harvard Medical School and a Howard Hughes Medical Institute investigator.
Sue McGreevey | EurekAlert!
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