An immune response that likely evolved to help fight infections appears to be the mechanism that drives human immunodeficiency virus (HIV) into a latent state, lurking in cells only to erupt anew, researchers at Duke Health report.
Published on November 14 in the journal Nature Microbiology, the research team provides new insights into the vexing process that makes HIV particularly stealthy, but could also play a role in other viral infections.
The findings from senior author Bryan R. Cullen, Ph.D., professor in the Department Molecular Genetics and Microbiology at Duke University School of Medicine and colleagues offer important insights, pointing to a protein complex called SMC5/6, which is involved in a host cell’s chromosome function and repair.
HIV enters the body, infects the immune system’s CD4+ T-cells, then makes a genome-length DNA molecule that it integrates into a host cell chromosome where it is then copied to generate viral RNAs and proteins.
If this so-called DNA provirus is prevented from integrating into the host cell DNA, for example by a drug that blocks this process, then it fails to make any viral RNAs and proteins and becomes inert. In contrast, DNA proviruses that are able to integrate are normally able to drive a 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 result in latent infections, lying low until prompted to erupt into an active infection.
The researchers found that a molecule that shuts down SMC5/6’s silencing action showed promising results as a potential therapeutic strategy as it inhibited the establishment of latent HIV infections. Reactivated proviruses are vulnerable to natural immune system responses and anti-retroviral drugs.
