Does An MS Drug Hold The Key For HIV Treatment

November 19, 2020
by John Kelly, MD
Does An MS Drug Hold The Key For HIV Treatment

U.S. and Canadian researchers feel that fingolimod offers a new type of therapy in the fight against HIV.

According to an article in the PLOS Pathogens scientific review journal, Dr. Rachel Resop and her George Washington University and University of Montreal colleagues found through a plethora of test-tube experiments that the drug could affect multiple key steps in the HIV lifecycle.

Fingolimod, or Ginleya as it is called commercially, is an oral medication used for multiple sclerosis, causing the central nervous system to attack the body's immune system.

Why Did Researchers Test Fingolimod For HIV?

Fingolimod is an immunomodulatory drug that targets the S1P or Sphingosine-1-phosphate of the immune system. S1P has several roles in the cell-signaling system, such as cell growth and movement, survival and inflammation. These processes are not possible without the S1P binding to certain protein receptors – S1PR1 to S1PR5.

However, it is the S1PR1 and S1PR4 found on several subdivisions of CD4 T cells, which can lessen when agonists drugs bind to receptors and cause an effect inside the cells to block the receptors. How S1P signals the CD4 T cells and its impact on HIV-1 are still not clearly known.

Prior research does show that fingolimod lowers S1PR1 in lymphocytes, regulates S1P signals and changes the lymphocytes' natural movement, growth and cycle state.

That's why researchers like Resop wanted to see if the molecule affects the active and latent HIV infection. Perhaps fingolimod would hinder the HIV infection. They were able to use other research to test their hypothesis.

They looked at the way S1P signaling was entangled with establishing HIV infection. The researchers used the CD4 T cells of HIV-negative people that they then activated. They treated those cells with different fingolimod doses before they were infected with R5 or X4 tropic HIV-1. They approached it in this way because of how HIV binds to the CD4 receptor but also chooses to bind on the CCR5 and CXCR4.

They learned that using fingolimod on the cells as a pretreatment lowered the HIV-1 infection rate with the most significant drop (55 percent) in the highest dose. They also found that the drug didn't cause the cells to be less viable and still had an inhibitory effect.

As evidence shows, fingolimod has an impact on establishing HIV-1 infection by interfering with the signaling of SP1. The researchers also found the drug had an inhibitory effect on HIV's cell-to-cell transmission, which noted a significant decline in infection.

More experiments found the fingolimod inhibitory effect in the cell-to-cell transmission is the result of HIV's decline in infecting new cells.

Was it possible fingolimod could help lower the proviral DNA within the target cells and reduce latent infection? Researchers treated the infected cells with fingolimod from day 10 to 13 of the infection, which was then replaced with two antiretrovirals until day 17. Researchers found there was a 66 percent decline in latent HIV infection when fingolimod was used on the proviral DNA.

Researchers also learned that fingolimod had no effect when the latently infected cells were already established. Thus, the study noted fingolimod had no effect on the latent reservoir when antiretrovirals were used afterward.

Latency infected cells occur during HIV's cell-to-cell transmission, which means most of the fingolimod's role is the result of decreasing productive infection. The effect is seen in a decline incidence of latently-infected CD4 T cells.

The researchers also looked at if fingolimod could spark latent HIV itself or with the help of latency-reversing agents. The molecules could potentially find hidden HIV in cells where the viral load is present, but standard tests show undetectable levels. By kick-starting the latent cells, researchers saw them as a "shock and kill" cure strategy that could then be killed with antiretrovirals.

For 48 hours, the CD4 T cells were given fingolimod, either alone or with six different latency-reversing agents. After that, researchers measured the reactivated cells and noted that the drug did not hinder the latency-reversing agencies' ability to work as they were designed for.


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