Researchers at the University of Pittsburgh and collaborators report that restoring and improving gut health may be key to slowing HIV progression to AIDS. They published their findings “T cell activation is insufficient to drive SIV disease progression” today in JCI Insight.

The animal study, which was performed with simian immunodeficiency virus (SIV), demonstrated that tackling only systemic immune activation and inflammation when attempting to control disease progression and comorbidities isn’t effective. Instead, treatments should target the root cause of those problems and focus on healing the gut.

simian immunodeficiency virus
Simian Immunodeficiency Virus in 3D. [NIH/Wiki]

“It was a previous study with disappointing results that put us on the path to this latest discovery,” said lead author Cristian Apetrei, MD, PhD, professor of infectious diseases at Pitt’s School of Medicine and of infectious diseases and microbiology at the School of Public Health. “Every study so far targeting systemic inflammation by addressing immune activation has had short-lived results. Upon reflection, we realized those results told us something important: Inflammation generated by the virus damaging the intestinal lining is driven by a separate mechanism from immune activation. We just had to prove it.”

“Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury,” write Apetrei and colleagues.

“We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation.

“Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.”

Cristian Apetrei, MD, PhD,
Cristian Apetrei, MD, PhD

The hallmark of HIV infection is the hijacking of helper T cells to make copies of the virus. Scientists have focused on treatments that stop this replication process; however, virus suppression only “calmed” immune activation and inflammation but did not restore them to pre-infection levels.

For a quarter century, scientists have also known that the gut is an immediate target of HIV. Within weeks of infection, the virus depletes the vast majority of immune cells in the intestines that are the depository of immunologic memory and protect the gut against invading pathogens.

When these cells are destroyed, the intestinal lining gets damaged, and gut flora enter the bloodstream. People with the fastest progressing HIV have less healthy gut microbiomes and more intestinal lesions. But past thinking was that calming immune activation and stopping HIV replication was key to controlling disease progression, and that gut health was a sideshow.

No progression to chronic infection

When African green monkeys get SIV, the virus doesn’t cause the type of gut damage seen in humans and some other nonhuman primates, and they don’t naturally progress to chronic infection and AIDS. Apetrei and his team artificially induced persistently high levels of immune activation in the monkeys, but after more than 100 days, they still hadn’t progressed to chronic infection, something that would be expected in less than half that time in other species.

Ivona Pandrea, MD, PhD
Ivona Pandrea, MD, PhD

“In this study, we’ve directly demonstrated that intestinal dysfunction is the main determinant of systemic inflammation and disease progression,” said senior author Ivona Pandrea, MD, PhD, professor of pathology at Pitt Medicine and of infectious diseases and microbiology at Public Health. “This points to an urgent need for therapies aimed at preserving gut integrity to avoid accelerated aging, comorbidities, and premature death in people living with HIV.”

Pandrea and Apetrei, a wife and husband team, recently focused on two more pathways that may be involved in the SIV-related gut dysfunction: an excessive release of neutrophil extracellular traps, which usually protect against infection, but may damage the gut while capturing viruses and microbes, and alterations in the adenosine pathway, a potent modulator with anti-inflammatory properties that may protect the gut.

“The issue is that we don’t know yet all the mechanisms responsible for gut damage in HIV infection,” Pandrea said. “We plan to test the role of these pathways in vivo.”

The team suggests that their findings should also prompt studies testing whether attempting to heal the guts of people living with HIV through diet, pre- and probiotic supplements, and gut microbial transplants slows the progression of the virus. Some of these strategies are being tested in their labs.

Other labs involved in the research include those at Tulane University, Rush University Medical Center, and the Los Alamos National Laboratory.

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