Chronic T cell immune activation and inflammation are key features of HIV-1 infection in humans and simian immunodeficiency virus (SIV) infection of rhesus macaques, and a group of researchers from University of Pittsburgh looked to see if T cell activation is sufficient to drive SIV disease progression.
In the study, published in JCI Insight in July 2023, the research team investigated the mechanisms of SIV disease progression (or lack thereof) in SIV-infected NHPs that are natural hosts of SIVs. They did this by inducing high and persistent levels of T cell immune activation in the absence of mucosal dysfunction and chronic inflammation in a model that naturally lacks SIV disease progression.
“This was actually a partially failed study,” explains study lead Cristian Apetrei, associate professor in the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine. “Our goal was to deplete the regulatory T cells in order to increase control by the immune responses and investigate the outcome of the outcome of the infection. We only partially depleted the regulatory cells; we did not significantly impact the immune responses and we only partially altered the outcome of the infection because we saw an increased activation of the T cells, but not of the systemic inflammation.”
Then, in a discussion related to the mechanisms by which HIV induces AIDS, someone stated it is very difficult to discriminate between the role of the T cell activation and the gut damage as triggers of the deleterious consequences of HIV. It was then the researchers realized what the results truly were, because they had exactly that.
“Our most important finding is that, in the absence of a severe gut damage that would result in an increase of the systemic inflammation, HIV and SIV infection do not progress to AIDS,” Apetrei says. “The corollary of which is that if we want to control disease progression and the comorbidities associated with HIV infection—even in people on ART—we should develop strategies to heal the gut, which is getting rapidly damaged in HIV infection.”
The authors looked at conventional parameters of HIV infection, including viral replication (viral load), CD4 T cell counts and their immune activation status; biomarkers of gut damage and hypercoagulability. What they learned was chronic T cell activation induced by Ontak does not result in persistent increases in coagulation markers in the absence of gut damage in SIV-infected AGMs.
“Retrospectively speaking, now that we understood what happened, there is nothing surprising about the results,” Apetrei says. “In reality, we were surprised to see that even with a partial depletion of the regulatory cells, we altered the system so much and nothing spectacular happened.”
While he admits that the follow-up of the study was relatively short and had the researchers utilized high levels of T cell activation for a longer period, they may have observed progression to AIDS.
“While this is a plausible scenario that cannot be dismissed, previous studies in which we directly induced mucosal lesions in SIV-infected AGMs provided clear indications of biological changes that had the potential to lead to both comorbidities and progression to AIDS within a much shorter time frame than the current study,” he said.
The future goal for the researchers is to be able to apply therapies to heal the gut to HIV-infected individuals.
“We are now able to control virus replication and thus the opportunistic infections,” Apetrei says. “There is still a certain level or residual inflammation which is responsible for the accelerated aging and comorbidities nowadays.”
To accomplish that, the team will start seeking drugs that can heal and improve the gut and use those to treat patients with inflammatory bowel diseases.