Researchers provide new insight into the frustrating process that makes HIV stealth

Researchers provide new insight into the frustrating process that makes HIV stealth

An immune response that likely evolved to help fight infections appears to be the mechanism that pushes the human immunodeficiency virus (HIV) into a latent state, hiding in cells to burst out again, Duke Health researchers report. .

Publication on November 14 in the journal Natural microbiologythe research team provides new insights into the vexing process that makes HIV particularly stealthy, but which may also play a role in other viral infections.

HIV has been shown to be incurable due to a small number of latently HIV-infected T cells that are unaffected by both antiviral drugs and the immune response.”

Bryan R. Cullen, Ph.D., Senior Author, Professor, Department of Molecular Genetics and Microbiology, Duke University School of Medicine

“These very long-lived cells can spontaneously emerge from lag and begin producing HIV even years after infection, necessitating the lifelong use of antiretrovirals,” Cullen said. “The origin of these latently infected cells has remained unknown despite considerable efforts.”

Cullen and his colleagues’ findings offer important insights, pointing to a protein complex called SMC5/6, which is involved in the function and repair of a host cell’s chromosomes.

HIV enters the body, infects CD4+ T cells of the immune system, then manufactures a genome-length DNA molecule which it integrates into a chromosome of the host cell where it is then copied to generate viral RNAs and proteins.

If this so-called DNA provirus is prevented from integrating into the DNA of the host cell, for example by a drug that blocks this process, it no longer makes viral RNA or proteins and becomes inert. In contrast, integrating DNA proviruses are normally able to cause productive HIV infection.

Cullen and his team found that in a small number of infected cells, the SMC5/6 protein complex initiates a process that silences the DNA provirus before it integrates into a host cell chromosome. These proviruses remain inert even after integration and lead to latent infections, remaining weak until induced to burst into an active infection.

“Our research suggests that latency does not result from intrinsic properties of infecting HIV, but rather an unfortunate side effect of a cellular innate immune response that likely evolved to silence invading foreign DNA,” Cullen said.

The researchers found that a molecule that stops the silencing action of SMC5/6 showed promise as a potential therapeutic strategy because it inhibits the establishment of latent HIV infections. Reactivated proviruses are vulnerable to natural immune system responses and antiretroviral drugs.

“Although antiretroviral therapies can reduce the viral load in AIDS patients below the level of detection, these drugs fail to eradicate HIV-1,” Cullen said. “Although considerable effort has been made to try to develop therapies capable of activating latent HIV-1 and to help antiretroviral therapies clear the body of infectious virus, these efforts have so far failed to to identify drugs that are both effective and non-toxic. Our represents a potentially important step towards achieving this goal.”

“Clearly, understanding the mechanism that drives HIV-1 latency can provide insight into how latent HIV-1 proviruses can be reactivated and then destroyed,” Cullen said.

In addition to Cullen, study authors include Ishak D. Irwan and Hal P. Bogerd.

The study received funding from the National Institutes of Health (R21-AI157616) and the Duke Center for AIDS Research (P30-AI064518).

Source:

Duke University Medical Center

Journal reference:

Irwan, ID, et al. (2022) Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency. Natural microbiology. doi.org/10.1038/s41564-022-01264-z.

#Researchers #provide #insight #frustrating #process #HIV #stealth

Leave a Comment

Your email address will not be published. Required fields are marked *