How Does HIV Mask Itself from Immune System Responses?

Developing effective human immunodeficiency virus (HIV) treatments and potential vaccines has consistently been a challenge, and new findings by researchers at the University of Bonn in Germany may explain why. They discovered how the virus masks itself in order to avoid immune system responses and documented the research in Nature Immunology.

The immune system’s first line of defense against HIV uses receptors to detect foreign structures, such as the genetic material of a virus. The cellular molecule, cGAS, senses that genetic material which immediately causes a cascade and immune system responses are activated. It has been believed that cGAS can only detect viruses which have double-stranded DNA — a characteristic that many have. The HIV-1 virus, however, consists of RNA which is always single-stranded even when multiplied and transcribed in human cells into DNA. Despite this, the team revealed that the HIV-1 virus also triggers a cGAS cascade – but how? Single-stranded DNA can create “hairpin” structures which resemble double-stranded DNA which are then detected by the cGAS sensor.

“The hairpin structures which can form in the case of HIV-1 are actually too short to be detected by cGAS,” senior author Martin Schlee, from the Institute of Clinical Chemistry and Clinical Pharmacology at the university, said in a news release.

If the pieces are too short, how is cGAS able to identify them? The researchers went on to explain that cGAS also has the ability to detect guanosines, which are special building blocks within the single-stranded DNA. The cellular response significantly increases because of this.

“If we remove the guanosines from these structures, the cells can no longer react to the single-stranded DNA. By contrast, if we add in additional guanosines, cells react more strongly,” explained lead author Anna-Maria Herzner.

It seems that the immune system chose to get rid of the guanosines in the DNA of HIV-1 viruses. Known as “elite controllers,” some patients naturally permanently suppress the virus to undetectable levels — which previous research has hypothesized could be due to guanosines. Therefore, the HIV genetic material seems to be detectable in the immune cells.

These findings open the door to further understanding the complex virus and possibly developing effective treatments.