Researchers provide new insights into the perplexing process that makes HIV stealthy

An immune response that likely evolved to help fight infection appears to be the mechanism that drives the human immunodeficiency virus (HIV) into a dormant state, lurking in cells only to flare up again, Duke Health researchers report.

Publication on November 14 in the magazine microbiology of naturethe research team provides new insights into the troublesome process that makes HIV particularly stealthy, but could 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 either antiviral drugs or the immune response.”

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

“These cells, which are very long-lived, can spontaneously emerge from dormancy and begin to produce HIV even years after infection, requiring lifelong use of antiretrovirals,” Cullen said. “The origin of these latently infected cells remains unknown despite considerable effort.”

Cullen and his colleagues’ findings offer important information, pointing to a protein complex called SMC5/6, which is involved in host cell chromosome repair and function.

HIV enters the body, infects CD4+ T cells of the immune system, then produces a genome-sized DNA molecule that integrates into a host cell’s chromosome where it is then copied to generate viral RNA and proteins.

If this so-called DNA provirus is prevented from integrating into the host cell’s DNA, for example by a drug that blocks this process, then it cannot produce viral RNA or protein and becomes inert. In contrast, DNA proviruses that can integrate normally can drive a productive HIV infection.

Cullen and his team discovered 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’s chromosome. These proviruses remain inert even after integration and result in latent infections, staying hidden until called upon to break out into an active infection.

“Our research suggests that latency is not due to any intrinsic property of the infecting HIV, but rather to an unfortunate side effect of an innate cellular immune response that likely evolved to silence invasive foreign DNA,” Cullen said.

The researchers found that a molecule that turns off the silencing action of SMC5/6 showed promise as a potential therapeutic strategy, as it inhibited 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 detection level, these drugs fail to eradicate HIV-1,” Cullen said. “While considerable effort has gone into trying to develop therapies that can activate latent HIV-1 and help antiretroviral therapies clear the infectious virus from the body, this effort has so far failed to identify drugs that are effective and not toxic. Our study represents a potentially important step toward achieving this goal.”

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

In addition to Cullen, the study’s 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).

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Magazine reference:

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

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