A recent discovery prompts a different approach in HIV cure research
Positively Aware Richard Jeffreys
Richard Jefferys @TAGHIVscience

Susana T. Valente is Associate Professor, Department of Immunology and Microbial Sciences (IMS), at the Scripps Research Institute in Florida. Valente’s research group is investigating an inhibitor of the HIV-1 Tat protein named dCA, with the goal of suppressing the ability of latent viruses to reactivate—ideally, permanently. A recent presentation by Valente at the 9th IAS Conference on HIV Science (IAS 2017) is available on YouTube.

There has been a great deal of focus on activating latent HIV in cure research, what is different about your approach?

The difference in the “Block and Lock” approach is that it is exactly the opposite of “Shock and Kill.” We intend to suppress the virus to a point that it is very difficult for the virus to reactivate and reinitiate infection.

A key feature of Tat inhibitors is that they can reduce viral RNA and protein production from already infected cells. Other antiretrovirals used in the clinic today are extremely potent and very efficient, but they can only stop new infections, they can’t stop already infected cells from producing viral RNA, proteins, and virus.

Have the results been encouraging so far?

In the humanized mouse model of HIV-1 latency the results have been extremely encouraging. When combining our Tat inhibitor with ART [antiretroviral therapy] we observed impressive reductions in the production of viral RNA from tissues [compared to ART alone).

When treatment was interrupted, we observed a nice delay in viral rebound. These results confirm the activity of the drug in vivo and confirm the mode of action, meaning, the HIV-1 promoter becoming increasingly epigenetically repressed over time [essentially, the part of HIV responsible for initiating the production of new viruses gets increasingly shut down], resulting in this delay in viral rebound.

Future studies will investigate the relationship between the duration of dCA treatment with time to rebound. The inclusion of this Tat inhibitor in current antiretroviral therapies could result in a full shutoff of the virus production, reducing the pathogenic effects of the residual viremia [virus production] that is still observed in the presence of ART.

We speculate that over time transcriptional repression of the HIV-1 promoter could be pushed passed a certain threshold where viral reactivation is extremely difficult to overcome.

In the future one could envision a situation with infected individuals using a single drug, or for example, being able to take breaks from therapy without immediate viral rebound.

Another benefit of Tat inhibitors is that by reducing viral RNA production from infected cells, infected individuals may be able to experience less morbidities associated with persistent levels of immune activation caused by low level viral protein production observed even under suppressive ART.

Do you think the compound you are using can be safe in people? Has it been tested in any animals?

So far it has been tested in mice, and we are in the process of testing it in rhesus macaques. Future studies will address safety in humans.

Are there plans to conduct clinical trials with this or similar compounds, and if so do you have a sense of when it might be feasible to begin?

A lot of safety studies will have to be performed before initiating clinical trials, but that’s where we are heading. The road to clinical trials is more of a job for big pharma; if we partner with them things can go faster.