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Trying to solve mystery of CD8 T cells and HIV
Some killer cells seem more potent
HIV research increasingly points to a connection between CD8 T cells and suppressed virus, but precisely how this works remains a mystery.
"We haven't figured that out yet," says Joel N. Blankson, MD, PhD, an associate professor at the Johns Hopkins University School of Medicine.
"We're trying to find out what the mechanism is for effective killing," Blankson says. "You look in the test tube and observe how quickly CD8 T cells kill and what the mechanism is."
Investigators have learned some information about CD8 T cells and their impact on HIV from observations made of elite suppressor case studies, including cases in which an elite suppressor has some sort of disease or treatmentseparate from HIVthat impacts his or her immune system.
It would be easier if they could create clinical trials or an animal model that would duplicate these immune problems, but this isn't an option, Blankson notes.
"So we have to take advantage of case reports when we find them," he says.
Researchers are finding that in elite suppressors, CD8 T cells kill very quickly and efficiently and make large amounts of granzyme B, a molecule that kills target cells, Blankson says.
"This is a whole new conceptlooking at the CD8 cell response," Blankson says.
So it might take a happy accident and discovery of a case study that sheds new light on the impact of CD8 T cells on HIV in elite suppressors. Something similar happened with a case study in which an elite suppressor patient had to receive rituximab-based chemotherapy that was shown to have no impact on his viral load, despite the drug's known impact on reducing immunity.
"We've seen a few elite suppressors where CD4 T cells start to decline even when they have no viral replication we can detect," Blankson explains.
"These patients have no viral replication, but still have a CD4 decline, and we think it might be due to immune activation," he adds. "We put them on antiretroviral therapy, and what we found was their CD4 T cells stabilized over time, and they have a lot less immune activation than they had before."
If research can pinpoint the fine details of how elite suppressors' CD8 T cells do such a superior job of protecting these people against HIV disease, then they could exploit that knowledge and use it in vaccine development, suggests Stephen A. Migueles, MD, CAPT, USPHS, senior clinical investigator and staff clinician in the HIV-Specific Immunity Section of the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH in Bethesda, MD.
"If, for instance, it is shown that their CD8s are functionally better because they bind better to HLA-peptide complexes, we could potentially model a vaccine to induce CD8 responses with those properties," he says. "As suggested in some recent reports in the monkey model of SIV infection, a good CD8 response alone might even prevent infection."
Induction of good cellular immune responses in addition to good antibody responses with a prophylactic vaccine may be desirable since the former might complement the latter by controlling virus replication in those who do get infected, Migueles says.
"This would potentially prevent disease progression and limit the transmission of antibody-resistant escape mutants," he adds.
If scientists were able to induce a similar CD8 T cell response in patients who progress typically with HIV, then they might be able to convert them into long-term nonprogressors or elite suppressors, Blankson says.
"A lot of evidence has shown that the [elite suppressor's] CD8 T cells are important, but why they are so much more effective is a mystery," Blankson says.