Inactive HIV Engages in Continuous Battles with the Immune System of the Body

For the past two decades, HIV research has predominantly focused on the idea that antiretroviral therapy can effectively eliminate active viruses causing severe infections while leaving a hidden reservoir of infected cells, invisible to the immune system until treatment discontinues, leading to a resurgence of the virus. Two recent studies, however, have uncovered that the virus continues to engage with the immune system, even during treatment. Some infected cells release fragments of viral RNA and protein that trigger an immune response, as reported in the September 13 issue of Cell Host & Microbe.

While not infectious, those damaged viral particles appear to weaken the immune system. The discovery provides a possible explanation for what allows the virus to reemerge with such vigor when people stop taking antiretroviral drugs.

The two new papers “cement — or should cement — that paradigm shift,” says immunologist R. Brad Jones of Weill Cornell Medicine in New York City, who coauthored an accompanying perspective in the same journal. Notes Steven Deeks, an HIV expert at the University of California, San Francisco School of Medicine: “No one actively questioned the presence of an active reservoir, but here [the researchers] find evidence that it might in fact matter.”

The studies are sobering news in the larger effort to cure HIV because the results show that the immune system is seeing but failing to successfully respond to the viral proteins, even when the virus’s replication is stopped with medication. It makes “our job much harder,” says immunologist Lydie Trautmann of the Henry M. Jackson Foundation for the Advancement of Military Medicine in Bethesda, Md. But it also offers a glimmer of hope: The new findings suggest a path toward figuring out how to make the immune response to HIV more effective, she says.

Both studies took blood cells from people on HIV antiretroviral therapy and looked for evidence of viral activity. Virologist Mathieu Dubé and colleagues used fluorescent RNA probes to look for viral genes in immune cells called helper T cells, a primary target for the virus. “We run 10 million cells, and the machine will detect which one is positive for HIV and which one is negative,” says Dubé, of the University of Montreal Hospital Research Center. The researchers then analyzed the infected cells, searching for viral RNA and protein production.

One surprise, Dubé says, was the large number of cells that were producing viral proteins. “We expected to see some spontaneous expression in a couple of cells, but not in so many.” The cells weren’t actually making new intact and infectious viruses; instead “most of what we found was defective — what we call junk,” he says. Another surprise was that even T cells that contained defective HIV genes, such as those with big chunks of DNA missing, were still able to produce viral proteins.

The key finding is that these junky viral proteins are a big biological problem. “Even though they are defective and do not trigger infection, they can still drive immune responses,” Dubé explains. And not in a good way.

In a healthy immune system, certain T cells would respond to the viral proteins by turning into specialized killer T cells capable of pouncing on and eradicating any HIV-infected cells. But in people with HIV, the immune cells fail to become potent killers, Trautmann’s team’s research shows.

Her interpretation: There are enough viral bits floating around to keep the immune system running ragged. Immune cells that should lead the attack on the virus are being asked to run marathon after marathon without ever stopping, she says. “They can’t keep up.”

The new results do suggest two possible strategies for better treating people infected with HIV. One is redoubling efforts to dramatically shrink the reservoir of infected cells, which could reduce the production of the problematic viral particles. The other is to figure out ways to reinvigorate T cells, perhaps by applying lessons from successes in boosting the immune response to cancer (SN: 10/1/18). If the T cells are more capable, then the bits of viral protein floating around could have a vaccinelike effect, keeping the immune system primed to control any new viral production more effectively, says Deeks, who was not involved in the research.

But both strategies are challenging. “We’ve come a long way, but the problem we have left is a tough one,” says Jones.

The research findings presented in these two studies represent a significant shift in the HIV research landscape, prompting experts to reevaluate the long-standing belief that the virus remains dormant during treatment. These studies may pave the way for innovative approaches to managing HIV infection, ultimately leading to more effective treatments and, potentially, a step closer to finding a cure.

The implications of these findings are profound. They underscore the complexity of HIV infection and the ongoing interactions between the virus and the immune system. While the road to a cure remains challenging, these discoveries offer a glimmer of hope for improving treatment and potentially finding new ways to harness the immune response against HIV.

In conclusion, the HIV research community is at a turning point, armed with fresh insights into the virus's behavior during treatment.

This triumvirate of evidence, as presented in these two studies, provides a robust and comprehensive understanding of the virus's interaction with the immune system, even during antiretroviral therapy.

The studies shed light on the challenges ahead but also suggest potential avenues for future research and therapeutic interventions.

Source : [Study Link - www.sciencenews.org]