Researchers Discover How HIV Integration into T-Cells Triggers Cell Death

Viral integration into CD4 T-cells triggers host cell death by activating DNA-dependent protein kinase (DNA-PK), according to study findings published in the June 5, 2013, advance online edition of Nature. Learning how HIV signals infected cells to die may lead to new ways to prevent immune system decline.

Arik Cooper from the National Institute of Allergy and Infectious Diseases and colleagues found that this did not occurwith mutant virus that lacks integrase. The integrase inhibitor raltegravir (Isentress) also blocked this cell-killing effect, as did pharmacological inhibition of DNA-PK. Reducing DNA-PK activation could improve CD4 cell survival -- but could also facilitate establishment of an HIV reservoir in surviving latently infected cells.

Below is an edited excerpt from a National Institutes of Health media advisory briefly describing the research and its findings.

NIH Scientists Discover How HIV Kills Immune Cells

Findings Have Implications for HIV Treatment

June 5, 2013 -- Untreated HIV infection destroys a person’s immune system by killing infection-fighting cells, but precisely when and how HIV wreaks this destruction has been a mystery until now. New research by scientists at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, reveals how HIV triggers a signal telling an infected immune cell to die. This finding has implications for preserving the immune systems of HIV-infected individuals. 

HIV replicates inside infection-fighting human immune cells called CD4+ T cells through complex processes that include inserting its genes into cellular DNA. The scientists discovered that during this integration step, a cellular enzyme called DNA-dependent protein kinase (DNA-PK) becomes activated. DNA-PK normally coordinates the repair of simultaneous breaks in both strands of molecules that comprise DNA. As HIV integrates its genes into cellular DNA, single-stranded breaks occur where viral and cellular DNA meet. Nevertheless, the scientists discovered, the DNA breaks during HIV integration surprisingly activate DNA-PK, which then performs an unusually destructive role: eliciting a signal that causes the CD4+ T cell to die. The cells that succumb to this death signal are the very ones mobilized to fight the infection. 

According to the scientists, these new findings suggest that treating HIV-infected individuals with drugs that block early steps of viral replication -- up to and including activation of DNA-PK and integration -- not only can prevent viral replication, but also may improve CD4+ T cell survival and immune function. The findings also may shed light on how reservoirs of resting HIV-infected cells develop and may aid efforts to eliminate these sites of persistent infection.

6/6/13

Reference

A Cooper, M García, C Petrovas, et al. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature. June 5, 2013 (Epub ahead of print).

Other Source

National Institute of Allergy and Infectious Diseases.NIH Scientists Discover How HIV Kills Immune Cells. NIH News press release. June 5, 2013.