A newly published review by Lennice Castro and Matthew Daugherty from the University of California San Diego provides a detailed look at a mechanism of cell death that researchers are attempting to exploit in HIV cure research. The mechanism involves certain proteins that can innately sense the presence of components from pathogens (like viruses) inside a cell, triggering a cascade of signals that ends with the demise of the infected cell by pyroptosis.
One such protein, CARD8, can sense the activity of the HIV protease enzyme. The normal task for HIV protease is to act as a scissor, cleaving apart viral proteins to assemble new virions (virus particles). As explained in the review, CARD8 contains mimics of the sites that HIV protease typically cuts, and if the CARD8 protein is cleaved by mistake it precipitates cell death.
Under normal circumstances, however, HIV protease avoids this cellular booby trap by remaining inactive until the end of the viral replication cycle when newly-made viruses are in the process of exiting the cell (see the HIV life cycle diagram from HIV i-Base).
In recent years, scientists — including researchers at the drug company Merck — have discovered that some antiretrovirals in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class have the capacity to prematurely activate HIV protease inside virus-infected cells, which leads to recognition by CARD8 and the initiation of the signaling cascade that ends with cell death by pyroptosis.
Merck is now actively pursuing the development of novel NNRTIs that trigger this mechanism, based on the theory that it could lead to the progressive clearance of the reservoir of HIV-infected cells that persists in people on standard antiretroviral therapy (ART). The company describes these new candidates as Targeted Activator of Cell Kill (TACK) molecules, and earlier this year they published laboratory work identifying lead candidates in the journal Science Translational Medicine.
The researchers tested a TACK molecule — codenamed Pyr01 — for activity against HIV-containing CD4 T cells sampled from people on ART and found that virus production (as measured by the HIV p24 protein) was decreased by 94-97%, with no effects on the viability of uninfected cells.
In a separate paper published last year, Merck researchers also identified compounds called DPP9 inhibitors that activate CARD8 and synergize with NNRTIs that have TACK activity.
The hope is that these candidates can be moved into clinical trials, but Merck has not yet publicly disclosed a timeline for when this may occur.
Whether any licensed NNRTIs can achieve levels sufficient to mediate killing of HIV-infected cells is uncertain. In their paper describing TACK molecules, the Merck researchers write:
“For currently approved NNRTIs, the selective HIV-1–infected cell death activity is much less potent than their RT [reverse transcriptase] inhibition activity, and this secondary effect is unlikely to be observed at a clinically achievable dose.”
But one of the papers cited in support of this statement leaves open the possibility that efavirenz (EFV) and rilpivirine (RPV) could exert the activity at standard doses:
“In NNRTI-treated patients, NNRTI plasma concentrations are in the range of efficient NNRTI-induced PR [HIV protease] cytotoxicity reported here. For example, EFV remains above 3.2 μM (1 μg/mL) and RPV remains above 0.4 μM (400 ng/mL). However, lower penetration of NNRTIs occur in peripheral compartments such as lymphoid tissues, which are primary sites of the HIV-1 reservoir.”
There have been some anecdotal suggestions that non-suppressible low-level HIV viral load is a less common phenomenon in people receiving efavirenz, but this hasn’t been proven (and the drug has known downsides in terms of tolerability). As Dr. Francesco Simonetti kindly noted in a tweet, work is ongoing in collaboration with the laboratory of Liang Shan (who pioneered this area of research) to investigate whether any licensed NNRTIs may also be capable of causing the death of HIV-infected cells.
The identification of methods to promote clearance of the HIV reservoir is obviously a priority for the HIV cure research field. Results so far with immune-based approaches have been mixed and generally underwhelming. The possibility of inducing the selective killing of HIV-infected cells with a known class of antiretroviral compounds is novel and encouraging, making this an area of investigation to watch. The mechanism would only be operational in cells when HIV is at least somewhat active and attempting to generate new virions, but recent evidence suggests that the HIV reservoir in people on ART is more active than was originally assumed. Ultimately, clinical trials will be needed to assess whether TACK molecules (or similar compounds) can significantly deplete the HIV reservoir in people on ART.
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