November 14, 2017
Strategies for dealing with the reservoir of latent HIV that persists despite antiretroviral therapy (ART) have primarily focused on awakening the virus from its dormant state. But Susana Valente and colleagues from the Scripps Research Institute in Florida are taking a different tack, flipping the idea of latency reversal on its head. Their approach -- which they have dubbed block and lock -- involves trying to imprison latent HIV in a way that prevents it from ever reactivating. The latest work by Valente's group was published recently in the open access journal Cell Reports.
The intervention Valente and colleagues are testing is Didehydro-Cortistatin A (dCA), an analogue of a natural substance isolated from the marine sponge Corticium simplex. Previous studies have shown that dCA inhibits the HIV Tat protein, and can have the effect of pushing the virus into a deep state of latency that is not reversed by T cell activation or latency-reversing agents in laboratory tests.
The new paper extends these results by testing the longer-term effects of dCA on latently infected CD4 T cells isolated from five HIV-positive individuals on suppressive ART. An initial evaluation found that the combination of dCA+ART led to greater suppression of HIV RNA production by the cells during prolonged culture when compared to just ART.
Another experiment maintained the cells for a 35-day period in culture in the presence of either ART or dCA+ART, then withdrew the treatments and stimulated the cells with the latency-reversing agent prostratin. HIV rebound occurred immediately in cultures that had been treated with ART, but viral reactivation was inhibited by an average of 99% in the cultures exposed to dCA+ART, with two participant samples showing 100% inhibition. The difference was statistically significant. Several other similar experiments found HIV rebound was significantly delayed and reduced as a result of dCA, including after activating cells with the mitogen PHA.
To gain insight into the potential in vivo relevance of the findings, studies were also performed in humanized mice infected with HIV. Treatment with dCA+ART was associated with 10.5-fold lower levels of HIV RNA in lymph nodes and seven-fold lower levels in brain tissue compared to ART, but differences in the spleen, bone marrow and peripheral blood mononuclear cells (PBMC) were not statistically significant.
A subsequent test also demonstrated that dCA+ART delayed HIV viral load rebound in HIV-infected humanized mice after treatment was interrupted, compared to ART. The latter group displayed evidence of recrudescing viral load at day three after interruption, extending to all eight animals by day 10. In contrast, among the dCA recipients, six out of 10 still had undetectable viral load at day 10. Viremia eventually became detectable in all the animals in the dCA group at day 19.
The researchers propose that dCA or similar Tat inhibitor compounds could have a role in providing additional suppression of HIV and limiting the formation of the viral reservoir if given in combination with early ART. They also suggest that, while dCA delayed rather then prevented HIV rebound after ART withdrawal in the current study, a greater duration of treatment might lead to more prolonged repression of viral reactivation from latency. The hope is that: "over time (in combination or not with other inhibitors), transcriptional repression could be pushed past a certain threshold where viral reactivation from latency is extremely difficult to overcome, blocking and locking HIV into sustained latency." Additional studies are planned in macaque models, with the goal of advancing the approach into clinical trials.
[Note from TheBodyPRO.com: This article was originally published by Treatment Action Group on Nov. 2, 2017. We have cross-posted it with their permission.]
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