Findings suggest that incomplete transcription causes latency in HIV infected cells.
HIV affects more than 1 million Americans, and while scientists have made progress in discovering effective new therapies, there is no known cure.
The virus can hide within cells, preventing the body’s immune system and antiretroviral therapy (ART) from detecting the infection. New findings highlight a need to understand the latency mechanisms of HIV in order to develop a treatment, according to a study published by Science Translational Medicine.
“Knowing what mechanisms keep these latently infected cells silent would help us develop a therapy to either wake them up and kill them or silence them permanently,” said lead author Steven Yukl, MD. “Until we figure out what keeps them latent, we can’t cure HIV.”
HIV takes over CD4 T cells of the immune system and rewires them to produce copies of the virus. A small portion of infected cells become latent instead of making viruses, according to the study. This dormancy not only remains a mystery to scientists, but makes it incredibly challenging to detect infected cells.
“We can’t even separate out uninfected from infected cells, let alone latently infected cells,” Dr Yukl said. “Latently infected cells are extremely rare—one in 1 million CD4 T cells—and we don’t know how to identify them.”
Latent cells can remain dormant for decades until they start producing copies of the virus in the absence of ART, according to the study.
Current HIV treatments are unable to kill latent cells or prevent them from reactivating in the future. ART may be able to prevent the virus from causing symptoms, but once the patient stops treatment, the virus rebounds.
Researchers have previously been able to imitate the entire infection process of HIV, including the latency stage, inside cloned laboratory CD4 cells. These cells, however, were not able to demonstrate the exact effects on the human body, according to the study.
In an effort to determine latency mechanisms among humans, the authors examined cells from 18 patients with HIV.
The findings disproved the previous belief that the inability of CD4 cells to convert HIV DNA into viral RNA, a process known as transcription, resulted in latency, according to the authors.
It was previously hypothesized that HIV DNA lived within certain cells but never converted into the viral RNA that triggers an immune response, the authors noted.
The researchers identified multiple fragments of viral RNA among latently-infected cells, proving that the conversion from DNA to RNA had begun.
The RNA fragments were discovered to be short or incomplete, meaning the conversion process was disrupted before completion, according to the study. The authors were able to activate the infected T cells and reverse the problems with transcription.
Experiments with latency-reversing agents showed that each agent helps complete a different process of transcription within CD4 cells. Therefore, a combination of these agents may be needed to reverse the latency of certain infected cells, according to the study.
“One of the nice things about knowing all these mechanisms is that we can look for new drugs or combinations and test how well they can overcome these transcription blocks,” Dr Yukl said. “It provides a roadmap to design and evaluate new therapies.”