Src and Syk kinase attenuation of HIV infection

A recent paper in The Journal of Immunology (2007, p2862) (no DOI?) concerning the role which two kinases (Src and Syk) play in the early steps of HIV infection, is interesting in a number of ways. Firstly, it reveals how these kinases might attenuate the infection early-on and second, it shows how a drug might have a completely unexpected adverse effect.

HIV, in most cases, enters the body by hitching a ride in dendritic cells (DCs) which are located in the mucosal lining of exposed tissues. The virus doesn’t infect these cells, it merely binds to cell surface receptors (eg. the mannose receptor or DC-SIGN) and is internalized into endolysosomal vacuoles. Migration of the DCs to the lymph nodes where the virus is passed on to CD4+ T-cells initiates the actual infection.

Tremblay and co-workers found that if inhibitors of the Src or Syk kinases, PP2 and piceatannol, were present during the transfer of the virus from the DCs to the CD4+T-cells (in cell culture) that the overall amount of virus that was present, afterwards, was higher than in their absence. The same result occurred if they used siRNA to knockdown the kinases. After additional experiments it was apparent that the kinase-inhibitors were causing the DCs, themselves, to become infected.

One might conclude from these experiments, that under normal circumstances the kinases “protect” the DCs from becoming infecting, allowing them to act as passive transporters of the virus to the lymph-nodes. How this occurs can only be speculated. One idea offered by the authors is that the inhibitors cause the virus to be shuttled to the cytoplasm of the DCs instead of the endolysosomal vacuole, whereupon it infects the cell.

I am probably thinking too hard about this but…a question not addressed in this paper, is what would happen to a person who is at high risk of becoming infected with HIV if they were on a drug regimen that included a Src or Syk inhibitor? Would there chances of becoming infected increase?

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3 Responses to “Src and Syk kinase attenuation of HIV infection”

  1. kinasepro Says:

    I don’t know anything about CD4+ translation of the yadda yadda yadda, but far be it from me to let a blog entry on Kinase inhibitors go un-besmirched! I do pretend to know a thing or two about them in the chemblogosphere after all.

    So… Well… first fix structure plz: PP2 is ClC1=CC=C(C2=NN(C(C)(C)C)C3=C2C(N)=NC=N3)C=C1

    Second… Hmmm well, paper’s interesting I guess. I take it to say: kinases may be involved. But frankly – PP2 hits tons of kinases, mostly in the SRC family, but a number outside as well like ckit, and even abl, so isn’t it a bit hard to make any conclusions about target? (not so much your conclusions, but those in the paper) Also piceatannol is only about 1 uM @ Km on SYK. I don’t know anything about the selectivity of the latter – but certainly the non-kinase activity would be relevant to the article.

    I would put money on Ariad having some insanely selective SRC inhibitors and a collaboration using one of their compounds to investigate the theory would certainly be interesting… PP2? Umm… Not so much. Likewise with somebody like Rigel and SYK. I guess I’m just not impressed with their choice of inhibitors.

    Personally, I blame the French.

  2. walkerma Says:

    Structure corrected…there were no structures, chemical-formulas or references given for PP2, so I had to rely on what SciFinder gave.

    Virology is my field, not kinases…even so, I would have like to see them use more-active/selective agents. The title of the paper promises more than the experiments were able to deliver.

  3. Wavefunction Says:

    Piceatonnol looks a lot like resveratrol the wine molecule. I wonder if res also inhibit these (or other) kinases.

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