2023-09-13 17:00:08
HIV, the virus that causes AIDS, cannot be eradicated from the body. That is why people with HIV are required to take treatment throughout their lives to control the reserve of HIV-infected cells that can reemerge if treatment is interrupted.
These reservoirs were long thought to be dormant, but two independent groups of researchers present in the journal ‘Cell Host & Microbe‘ results from two studies showing that a subset of these cells spontaneously produce HIV RNA and proteins that can affect patients’ HIV-specific immune responses.
“It is a deceptively inactive virus,” says the immunovirologist Daniel Kaufmanof the Lausanne University Hospital (Switzerland) and University of Montreal (Canada), and lead author of one of the articles. «Even in people who receive treatment, HIV continues to have some activity and continues to interact with the immune system. “We need to understand whether these ongoing interactions have clinically relevant consequences.”
Previous studies have shown that when latent HIV reservoir cells are reactivated in the laboratory, they produce viral RNA and proteins, but it was unclear whether this phenomenon was occurring in people with HIV.
In order to resolve this mystery, the researchers obtained blood samples from 18 people with HIV who had been on antiretroviral therapy for more than 3 years.
They then used a laboratory method –RNA flow cytometry– to classify CD4+ or “helper” T cells (the type of cell that HIV selectively infects) based on whether they were infected with HIV and, furthermore, whether they were actively producing HIV RNA and proteins.
The researchers also characterized the T cells based on their function (for example, whether they were the type of helper T cell that fights intracellular viruses or the type that fights extracellular bacteria) to determine whether any CD4+ T cell subtype was more likely to harbor HIV reservoirs.
“Our technique allows us to observe individual cells to see if they contain the virus and what parts of the virus they express,” explains Mathieu Dubé, immunovirologist at the University of Montreal and first author of the article. «For each patient, we could estimate how many of these cells are still active and we could also look for associations between viral characteristics and cellular characteristics».
The researchers found that 14 of the 18 patients had HIV reservoirs that spontaneously produced viral RNA. In 7 of the 18, the viral reservoirs also produced viral proteins, including p24, a component of the HIV envelope.
“Most viruses that remain in the body are defective or junk viruses that can’t really multiply, but we found that these defective viruses can still produce viral RNA and sometimes proteins,” says Kaufmann.
Although these fragments of viral RNA and protein were non-functional debris, the researchers found that they were enough to stimulate an immune response. Since stronger HIV-specific immune responses were associated with more active HIV reservoirs, the researchers suspect that this immune response may be futile, but more research is needed to test that hypothesis.
«Data suggest that RNA and proteins produced by these viral reservoirs could be drivers of inflammation» -explica Kaufmann-.
In his opinion, this could be important because a “subset of people who are successfully treated with antiretroviral therapy for HIV still have negative consequences of living with the infection, for example, accelerated heart disease, frailty and premature osteoporosis.”
When they investigated which types of CD4+ T cells were most likely to harbor active viral reservoirs, they found that active HIV reservoirs were harbored in T cells with a variety of phenotypes and functions, although some types tended to carry more virus than others.
Although all patients in the study were white men, the researchers observed substantial variation among patients. They say future studies should further investigate these differences between patients and investigate HIV reservoirs in a more diverse set of patients.
The second article, directed by the immunologist Lydia Trautmannof the Vaccine and Gene Therapy Institute at Oregon Health and Science University (USA), has also seen that a subset of CD4+ T cells spontaneously express viral RNA during antiretroviral therapy, specifically in cohorts of Thai participants who initiated therapy in acute versus chronic infection. Fewer viral proteins were observed in patients with acute infection, but similar immune responses were observed between both groups.
“Our study suggests that residual immune dysfunction driven by the active HIV reservoir on antiretroviral therapies could contribute to the lack of viral control after discontinuation of analytical treatment by preventing the differentiation of self-renewing and functional HIV-specific CD8+ T cells that “they can mount quick and efficient recall responses,” the authors write.
Therefore, “HIV remission strategies will likely need to target transcriptionally active proviruses that produce viral proteins during antiretroviral therapies to harness HIV-specific CD8+ T cells to control viral rebound after cessation of therapy.”
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