A research team led by the Tokyo Medical and Dental University (TMDU) has succeeded in identifying a molecular compound that activates HIV-1 that lies dormant in cells, thus showing new promise for HIV treatment.
According to the EurekAlert news portal, operated by the American Association for the Advancement of Science, an inter-institutional research group managed to take a significant and promising step in the ability to treat HIV type 1 (HIV-1), the most common in the planet.
Latent viruses
At this point, it is worth remembering why it is so difficult to eliminate HIV-1 from the body. Although the replication of the virus can be counteracted by antiretroviral treatment, which is usually given as a combination of drugs, this therapy is not capable of completely curing HIV-1 infection.
This is because the virus forms latent infections in cells, where the virus remains present but inactive and therefore “hidden” from drug treatment, which does no harm to it. These infections are known as reservoirs.
Eradicating latent HIV-1 is the main obstacle to curing HIV, but now the Japanese research group has identified a compound that can activate these “hidden” viruses and allow the eradication of latent HIV reservoirs.
A strategy to activate the virus
Latency reversal agents (LRAs) are drugs that reverse the latency process and cause HIV activation. These drugs can be used in a strategy known as “shock and kill,” in which the substance “shocks” the virus, which comes out of hiding and is susceptible to removal.
Thus, the LRA causes a shock that reactivates the latent reservoirs of HIV, which can be eliminated by the immune system itself. However, although the use of LRA has previously been shown to be able to reactivate latent-infected cells, a reduction in the number of latent HIV reservoirs has not been observed.
In this study, the authors focused on YSE028, a derivative of a molecule called DAG-lactone. These molecules have already been studied to treat other health problems, such as cancer and Alzheimer’s disease. YSE028 activates a protein called protein kinase C (PKC) that has been shown to have a latency reversal effect, and has no significant toxicity to cells.
“A study we did previously showed that YSE028 was able to cause reactivation of dormant cells infected with HIV-1 and then induce cell death,” explained one of the research participants, Dr. Takahiro Ishii. “Therefore, we explored chemical derivatives that were structurally similar to YSE028 with even higher latency reversal activity.”
New tool, new possibilities
The team used a cell line called J-Lat 10.6, which are HIV-1-infected dormant cells that have been engineered to fluoresce green (via a protein) when activated. This green fluorescence can be observed, so that activated cells can be identified.
Many of the chemical derivatives developed did not show significant activity, but “compound 2” showed about ten times more latency reversal activity than YSE028.
The team was also able to identify characteristics that affected the qualities of the molecule, such as its affinity for binding to the PKC protein and its resistance to being broken down by certain enzymes that can affect the stability of the compounds.
According to the researchers, these data “will be very informative for the design of DAG-lactone derivatives that activate PKC, which could be key to HIV treatment,” said study lead author Dr. Hirokazu Tamamura.
The use of these new DAG-lactone derivatives, in combination with existing antiretroviral treatment and other ARLs, could bring science closer to a complete cure for HIV-1.
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