An old protein with a new anti-HIV role

There are many viruses that you can have yourself vaccinated against, and sometime, like in the case of small pox, the vaccination can completely eradicate the virus from the face of the planet. HIV, however, is not one of them. It changes frequently and has evolved into many different strains presenting with varying behaviour. These strains can be so different that some antiviral drugs can be efficient only against one of them but not another.

One of the ways these strains differ is how they enter cells. You can think of a cell as a large room with many doors leading to it. And of HIV virus as a small malicious robot that enters these rooms and consumes them from the inside to manufacture its own copies. To open the doors, the robots have specialised arms. However some strains of the virus have arms that can only pull handles, while others can only turn knobs. This is mirrored in anti-HIV medications. For example, following this analogy, some drugs act as attachments that you put on the knobs to give them rectangular shape. The knob-turning virus won’t be able to grab it and get inside the cell anymore. However, the same drug won’t affect the handles and therefore have no effect on the handle-pulling virus. There are also strains of HIV that can both pull handles and turn knobs, but that’s a different story.

A recent publication (1) has revealed that our platelets (the tiny cell-like structures in our blood responsible for clotting) can secrete quite large amounts a long known protein called platelet factor 4 (PF4) that actually gets in the way of HIV infection. It does so by a mechanism similar to the one of the drug turning a round knob into a rectangle, but this protein does not bind to the doors on the cells, but instead to the virus arms. The data suggests that PF4 does not attach to the “fingers” of the viral arm, but rather in some way grabs it by the wrist and gets in the way of it getting a hold of the handle. Or the knob for that matter, as the researchers have shown that PF4 can affect both handle-pulling and knob-turning HIV strains. However, HIV virus isolated from a small number of people seemed to be unaffected by PF4. And this is another example of HIV diversity – most of the analysed strains are inhibited by PF4, but some – are not.

The research is interesting for a few reasons. Firstly, it identifies an important part of the HIV “arm” – the wrist. Much research has been focused on the fingers or the handles/knobs as it is them that interact with each other directly. It was interesting to see how grabbing the wrist can also significantly affect the ability of the virus to open the doors. Secondly, as the authors point out, PF4 not only binds the viral arm, but also activates the immune system cells, which might in turn further facilitate fending off the virus. Thirdly, identifying a new way by which body’s own proteins interfere with viral infection can open some doors to development of new drugs. And finally, as mentioned before, it further highlights the diversity of HIV, as there was a small number of patients whose virus did not seem to have been affected by PF4. This in turn further underlines the fact that, unlike for many other viruses, HIV therapy should be personalised to the behaviour of the particular strain infecting the particular patient.

1. Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor.