For the past two decades, the primary focus in HIV research has been on antiretroviral therapy, which effectively suppresses the active viruses responsible for devastating infections. However, it leaves behind a hidden reservoir of infected cells that remain virtually invisible to the immune system—until treatment is discontinued, at which point the virus rebounds with extraordinary force.
Recent studies have unveiled a surprising revelation: the virus continues to engage the immune system even during treatment. Some of the infected cells release fragments of viral RNA and protein that trigger an immune response, as reported in the September 13th issue of Cell Host & Microbe.
Although these damaged viral particles are not infectious, they appear to weaken the immune system. This discovery offers a potential explanation for the virus’s resurgence when individuals cease taking antiretroviral drugs.
According to immunologist R. Brad Jones of Weill Cornell Medicine in New York City, co-author of an accompanying perspective in the same journal, these two new studies solidify a significant shift in our understanding of HIV. Steven Deeks, an HIV expert at the University of California, San Francisco School of Medicine, notes that while the existence of an active viral reservoir was not actively questioned, this research suggests that it may indeed be more significant than previously thought.
These findings present a challenge in the quest to cure HIV because they indicate that the immune system recognizes viral proteins but struggles to mount an effective response, even when viral replication is halted with medication. Lydie Trautmann, an immunologist at the Henry M. Jackson Foundation for the Advancement of Military Medicine in Bethesda, Maryland, describes this as a significant hurdle. However, she also sees a glimmer of hope: these results suggest a path toward improving the immune response to HIV.
Both studies involved examining blood cells from individuals on HIV antiretroviral therapy to detect evidence of viral activity. Virologist Mathieu Dubé and his team used fluorescent RNA probes to search for viral genes in immune cells called helper T cells, which are a primary target for the virus. Dubé explains that they examined millions of cells, identifying those positive and negative for HIV. Subsequently, they analyzed the infected cells to identify viral RNA and protein production.
A surprising revelation from this research was the significant number of cells producing viral proteins, even though they were not creating intact and infectious viruses. Most of what was discovered was deemed “junk.” Surprisingly, even T cells with defective HIV genes, such as those with missing chunks of DNA, were capable of producing viral proteins.
The critical finding is that these imperfect viral proteins pose a significant biological challenge. Although they are defective and incapable of causing infection, they can still stimulate immune responses. In a healthy immune system, specific T cells would transform into specialized killer T cells, capable of eliminating any HIV-infected cells. However, in individuals with HIV, these immune cells do not become effective killers, as demonstrated by research conducted by Trautmann’s team.
According to Trautmann, the implication is that there are enough viral fragments circulating to keep the immune system constantly engaged. The immune cells responsible for targeting the virus are pushed to their limits and are unable to keep up.
These new findings suggest two potential strategies for improving the treatment of HIV-infected individuals. One approach involves intensifying efforts to significantly reduce the reservoir of infected cells, which could lower the production of problematic viral particles. Another strategy is to find ways to reinvigorate T cells, potentially drawing insights from successful methods used to boost immune responses in cancer treatment. If T cells become more potent, the circulating viral protein fragments might have a vaccine-like effect, better priming the immune system to control any new viral production. This approach offers hope but is inherently challenging, given the complexity of HIV.
In the words of R. Brad Jones, “We’ve made substantial progress, but the challenge we face remains formidable.”
CITATIONS:
M. Dubé et al. Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV- specific CD4+ and CD8+ T cells. Cell Host & Microbe. Vol. 31, Sept. 13, 2023, p. 1507. doi: 10.1016/j.chom.2023.08.006.
H. Takata et al. An active HIV reservoir during ART is associated with maintenance of HIV-specific CD8+ T cell magnitude and short-lived differentiation status. Cell Host & Microbe. Vol. 31, Sept. 13, 2023, p. 1494. doi: 10.1016/j.chom.2023.08.012.
A. Herrera and R.B. Jones. Whack-a-virus: HIV-specific T cells play an exhausting game. Cell Host & Microbe. Vol. 31, Sept. 13, 2023, p. 1427. doi.org/10.1016/j.chom.2023.08.013.
