Dysfunctional cells are paving the way for more effective HIV treatment

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Photo Credit: Rachel Tyler | Daily Texan Staff

If you want to learn about your body’s immune system, you need to look at its control center — the lymph nodes. That’s where the various cells that comprise the immune system come together and communicate to devise a plan of action to fight whatever disease might be present in the body, said UT doctoral graduate Ben Wendel.

Wendel was the first author of a paper published in Science Immunology this month that outlined the discovery of an irregularity in the follicular T cells (Tfh) of HIV patients. These cells are a subset of CD4 cells, which are the cells in the immune system that are depleted by HIV. HIV treatments usually try and keep the CD4 cell count high, Wendel said. 

The interesting thing is that in patients with HIV, the Tfh cell count is actually higher than it is in healthy individuals, according to Ning Jenny Jiang, the principal investigator of the lab Wendel worked in. Yet those cells don’t help the patient produce antibodies for some unknown reason, and that became the question to solve. 

Jiang’s lab worked with Laura Su, an assistant professor of medicine at the University of Pennsylvania, and her lab to try and see why this was. Jiang’s lab used molecular identifier cluster-based immune repertoire sequencing, or MIDCIRS, while Su’s lab used mass spectrometry to analyze the cells. Mass spectrometry allows researchers to determine tissue composition by the mass of the chemicals that make them up.

Wendel was also the first author on the paper describing the development of MIDCIRS. The method uses molecular identifiers, small stretches of DNA, to tag each T cell’s RNA transcript. This helps researchers see where errors might have occurred during replication.

“We first developed (MIDCIRS) on the antibody side, and then adjusted it so that it could be used for T cells, and then we used that in this paper to track the antigen dependence of the Tfh cell properties,” Wendel said. 

The Tfh cells provide the signals necessary for B cells — the cells in the immune system responsible for creating antibodies — to mount an effective antibody response, Wendel said.

This prevents HIV-infected individuals from responding well to vaccines. Vaccines work by initiating an antibody response and building the body’s memory to protect against that disease if the individual is exposed to it again, but HIV patients don’t respond as well to vaccines as healthy individuals do, Wendel said. 

“There’s more going on between HIV and the immune system, (and) the CD4 count doesn’t paint the whole picture,” Wendel said. 

What they found this time around was that these Tfh cells are functionally disabled, meaning that they aren’t able to help B cells generate effective neutralizing antibodies, Jiang said.

“We essentially explored this new way that HIV can impact the immune system, and that could open up a new way to alleviate those issues,” Wendel said.

Current vaccines are focused on creating immunogens that induce neutralization antibodies but target just the B cells, but this new study suggests that Tfh cells also need to be taken into consideration when designing effective treatments, Jiang said.

“We’re still building; there’s still more work to do,” Wendel said.

The next logical step is to see whether it would be possible to reverse this abnormality, Wendel said. If it is possible to reverse the abnormalities, then that would help recover the vaccine response for HIV-infected individuals.

“This paper was just step zero, laying the foundation for any potential new, next-generation therapeutics for HIV,” Wendel said. “It’s uncharted territory.”