Protein Complex Behind HIV Latency Identified

Researchers from Duke University recently revealed how human immunodeficiency virus (HIV) utilizes an immune response to launch itself into a latent state within cells. The findings, recently published in Nature Microbiology, explain how a specific protein complex may be to blame for HIV’s ability to hide so well in the body.

“HIV has proven to be incurable because of a small number of latently HIV-infected T-cells that are untouched by both antiviral drugs and the immune response,” says senior author Bryan R. Cullen, Ph.D., professor in the Department of Molecular Genetics and Microbiology at Duke University School of Medicine. “These cells, which are very long-lived, can spontaneously emerge from latency and start producing HIV even years after infection, thus necessitating the life-long use of antiretrovirals.”

After entering the body, HIV infects CD4+ T-cells and integrates a genome-length DNA molecule with the host cell’s chromosome. Then, this new chain is copied to generate viral RNAs and proteins, creating “proviruses.” If these DNA proviruses were prevented from integrating with the host cell DNA, then it fails to make any viral RNAs or proteins.

Cullen and his colleagues investigated these molecular mechanisms in more detail in their work. They 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 with the host cell chromosome. Even after integration, these proviruses remain inert and result in latent infections, lying low until prompted to erupt into active infection once again.

“Our research suggests that latency results not from any intrinsic properties of the infecting HIV but rather from an unfortunate side effect of a cellular innate immune response that probably evolved to silence invasive foreign DNA,” Cullen says.

The team also identified a molecule that shuts down SMC5/6’s silencing abilities, showing promise as a potential therapeutic strategy for latent HIV infections. “Although antiretroviral therapies can reduce the viral load in AIDS patients to below the level of detection, these drugs fail to eradicate HIV-1,” states Cullen. “While there has been considerable effort expended on trying to develop therapies that can activate latent HIV-1 and help antiretroviral therapies clear the body of infectious virus, this effort has so far failed to identify drugs that are both effective and non-toxic. Our study represents a potentially important step toward achieving this goal.”

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