New evidence for NK cells as long-term host

A recent report in Proceedings of the National Academy of Sciences rekindles the debate on the role of natural killer (NK) cells in the maintenance of HIV infection during treatment, identifying a CD4-positive NK subset that remains infected with HIV in vivo despite long-term treatment with antiretrovirals.

Pools of inactive, latently infected, CD4 T cells that harbour HIV present a major obstacle to the eradication of the virus in patients receiving antiretroviral therapy. Moreover, certain studies have suggested the existence of other long-term reservoirs of the virus, since the kinetics and genetic identity of rebounding virus does not always correlate with the T-cell population.

Antonio Valentin and colleagues working in centres in Greece and Massachusetts, USA, have now identified a subset of NKcells that may also serve as a persistent viral store. These cells express NK markers, and the CD4 molecule, in addition to the CXCR4 and CCR5 proteins that facilitate HIV infection.

Firstly the authors showed that the NK cells can be infected with HIV in vitro, and that infection is dependent on the CD4 molecule. They then analysed this subset of cells from HIV-infected individuals, and found that HIV viral DNA is indeed present in these cells. Importantly, the virus derived from these cells was still infectious, implying that this subset could re-seed infection in vivo.

Finally, after following a group of HIV-positive individuals through the first 2 years of antiretroviral therapy, the researchers showed that the HIV-infected NK cells persist during this time, and carry substantial levels of latent viral DNA.

The research emphasizes the importance of ‘alternative’ viral reservoirs in maintenance of HIV infection, and prompts the consideration of such factors in the design of novel drugs. These calls are supported by reports suggesting that the protease inhibitor class of antiretroviral agents may not be effective in inhibiting viral replication inside NK cells.