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Researcher

This is the first evidence of knocking down (using a novel technique) components of pyroptotic cell death pathway in CD4 T cells, which block cell death and inflammation by HIV-1. The observed inhibition of cell death was comparable to treatment with retroviral inhibitors.
This is also the mechanistic link between CD4 T-cell death to chronic inflammation, two signature mechanisms propelling HIV pathogenesis.
The Science paper identifies the DNA sensor that activates caspase-1 and cell death in these target cells as IFI16. Was that also known since the ancient Pac-Man video game?
Lastly, VX-765 represents a new strategy to fight the disease, which target the host instead of the virus. This drug proved to block both cell death and inflammation by HIV.
I agree, it remains to be seen if these all will turn out to be as important as Warner Greene and colleagues are suggesting. Waiting for your follow-up blog in 5 years.

Richard Jefferys

Sorry to be so slow replying to your comment. I'd readily concede that I've given short shrift to the novel, careful and impressive work involved in these studies because of the fact that I feel that, based on the current evidence, their implications have been misleadingly oversold to the media and public.

Your comment doesn't address my primary concern: how many "bystander" resting CCR5-expressing CD4 T cells are there that can be killed by this mechanism in the setting of solely R5-tropic infection?

If I'm understanding it correctly, fig 2d of the Nature paper reports that 5.03% of the CD4 T cells in the HLAC expressed CCR5, and 81.87% of those cells expressed either one or both activation markers measured (CD25 and CD69). My math is dubious at the best of times, but I think that would leave something like 0.9% potentially resting CD4 T cells expressing CCR5. Which is a smaller proportion than they cite for productive infection. Unless I'm misunderstanding something, this would suggest that the amount of bystander CD4 T cell death in R5 tropic infection is likely to be less than that caused by productive infection and activation-induced cell death, at least in the tissue studied (granted, the proportion of resting CCR5-expressing CD4 T cells could be different elsewhere). Certainly, it suggests that the amount of bystander CD4 T cell death would be vastly less than the ">95%" seen with X4-tropic virus. But the researchers have now widely disseminated this factoid that ">95%" of CD4 T cell death in HIV infection involves bystanders, which I think is irresponsible and misleading because it only applies to X4 tropic HIV.

The title of the paper also says that pyroptosis drives CD4 depletion in HIV infection, and to me this limitation suggests that more evidence is needed to address the role of pyroptosis in R5 infection before such a conclusion can be drawn. The data certainly offer a very compelling explanation for the consistent association between X4 tropism and rapid CD4 T cell depletion.

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