For the past two decades, researchers in the field of HIV have believed that antiretroviral therapy effectively eliminates active viruses responsible for debilitating infections. However, this treatment leaves behind a concealed reservoir of infected cells that seemingly escape the immune system’s notice—until treatment is discontinued, allowing the virus to resurface with a vengeance. In a groundbreaking revelation, two recent studies published in the September 13 issue of Cell Host & Microbe have illuminated a previously hidden facet of HIV’s interaction with the immune system.

The Continual Challenge of HIV

Contrary to previous beliefs, these studies demonstrate that the virus continues to exert its influence on the immune system, even during antiretroviral treatment. Some infected cells produce fragments of viral RNA and protein, inciting an immune response. While these particles are non-infectious, they appear to weaken the immune system. This discovery offers a potential explanation for the virus’s resurgence when individuals cease antiretroviral drug therapy.

Paradigm Shift

Immunologist R. Brad Jones of Weill Cornell Medicine in New York City, a coauthor of an accompanying perspective in the same journal, asserts that these two studies solidify a paradigm shift in our understanding of HIV. According to Steven Deeks, an HIV expert at the University of California, San Francisco School of Medicine, the presence of an active reservoir was not actively questioned, but now there is evidence that it may indeed matter.

A Daunting Challenge

These findings present sobering implications for efforts to cure HIV, as they reveal that the immune system detects but struggles to effectively respond to viral proteins, even when viral replication is halted by medication. Immunologist Lydie Trautmann of the Henry M. Jackson Foundation for the Advancement of Military Medicine in Bethesda, Md., acknowledges that this discovery makes the task of combating HIV much more challenging. However, it also provides a glimmer of hope by suggesting a path toward enhancing the immune response to HIV.

Understanding the Research

Both studies conducted investigations on blood cells from individuals undergoing HIV antiretroviral therapy to uncover evidence of viral activity. Virologist Mathieu Dubé and his team employed fluorescent RNA probes to identify viral genes within immune cells known as helper T cells, which are primary targets for the virus. They then analyzed these infected cells, searching for signs of viral RNA and protein production.

Surprising Findings

One of the study’s surprises was the significant number of cells producing viral proteins. Even though these cells were not generating new, intact, and infectious viruses, they predominantly produced defective components, often referred to as “junk.” Furthermore, even T cells housing defective HIV genes, including those with substantial DNA deletions, remained capable of producing viral proteins.

The Problem with Junk

The crucial revelation from this research is that these defective viral proteins pose a substantial biological challenge. Despite their inability to initiate infection, they can still trigger immune responses, albeit unfavorable ones. In a healthy immune system, specific T cells would respond to these viral proteins by transforming into specialized killer T cells, which can eliminate HIV-infected cells. However, in individuals with HIV, immune cells fail to develop into potent killers, as demonstrated by Trautmann’s team’s research.

Overwhelming the Immune System

The implication here is that there are enough fragments of viral material in circulation to overburden the immune system. Immune cells that should be leading the charge against the virus find themselves constantly engaged in an unending marathon, unable to keep up with the viral onslaught.

Potential Treatment Strategies

Despite the challenges, these findings suggest two potential strategies for more effectively treating HIV-infected individuals. First, there is a need to intensify efforts to drastically reduce the reservoir of infected cells, which could limit the production of problematic viral particles. Second, researchers can explore methods to reinvigorate T cells, possibly drawing inspiration from successful approaches in boosting the immune response to cancer.

A Tough Road Ahead

Both of these strategies are formidable undertakings. As Jones notes, significant progress has been made, but the remaining problem is a complex and challenging one that requires further exploration.