The results of studies headed by George Washington University (GW) researchers suggest that an immunomodulatory drug called fingolimod, which is approved for treating multiple sclerosis (MS), blocks human immunodeficiency virus (HIV) infection and transmission in human immune cells, and reduces latent HIV reservoir. While additional studies in animals and humans will be needed to verify the findings, these early results hint that the drug may represent a promising novel therapy for HIV treatment and prevention.
“For the first time, our research team found that by targeting the receptors to the signaling molecule sphingosine-1-phosphate (S1P), we could effectively block HIV infection and cell-to-cell transmission of the virus and consequently reduce the seeding of the latent virus in the test tube,” stated Alberto Bosque, PhD, assistant professor of microbiology, immunology, and tropical medicine at the GW School of Medicine and Health Sciences. “We believe this compound may be a promising novel therapy for HIV treatment and prevention.” Bosque, together with postdoctoral fellow Rachel Resop, PhD, and colleagues, reported their findings in PLOS Pathogens, in a paper titled, “Fingolimod inhibits multiple stages of the HIV-1 life cycle.”
Nearly 40 million people worldwide currently live with HIV, and treatment remains lifelong because the virus can establish latency by integrating its genome into that of host cells, which then become quiescent until the virus reactivates at some future time, the authors wrote. “By establishing latency, HIV evades eradication by host defense mechanisms and drug treatment.”
HIV is currently managed by antiretroviral drugs, but these don’t specifically target latent infection, may have side effects, and are of limited use in preventing transmission of the virus between individuals. Discovering novel strategies to target HIV infection and latency is therefore “crucial”, the authors continued. “While antiretroviral drugs have been effective in treating HIV thus far, drug resistance, negative side effects of antiretroviral therapy, and its varying efficacy underscore the need to develop alternative treatment and prevention options,” said Bosque.
Current antiretroviral therapy (ART) primarily consists of drug classes that target various stages of the viral life cycle, including inhibitors of entry, protease, integrase, and reverse transcriptase. The researchers reasoned that another potential approach to treating HIV infection is the use of immunomodulatory compounds directed toward a component of the immune system. This tactic could potentially be effective for a wide range of individuals, and avoid some of the off-target effects of ART. However, they pointed out, to date, immunomodulatory compounds that target innate immune factors haven’t been extensively characterized for HIV therapy.
The researchers focused on FTY720, a compound that is better known as fingolimod or Gilenya. The immunomodulatory drug acts by blocking the action of sphingosine-1-phosphate (SIP) receptors, a component of the immune system involved in the progression of infection. Interestingly, it has previously been proposed that sphingolipids might be involved in various stages of the HIV-1 life cycle, the team noted, and prior studies had observed the potential for an S1P receptor agonist to reactivate HIV from latency, and that chronically infected individuals demonstrated a decreased response to S1P signaling, the team noted.
However, they pointed out, “ … the role of S1P signaling in establishment of infection and the potential to modulate this pathway to alter the course of infection or prevent establishment of the latent reservoir in CD4 T cells had not been reported.”
Fingolimod is clinically approved for treatment of multiple sclerosis, and is well-tolerated when taken orally on a daily basis. “FTY720 has activity at four of the five S1P receptors (S1PR1, 3, 4, and 5) and has been shown to cause downregulation of S1PR1 in lymphocytes and act as a modulator of S1P signaling …” the team noted. “Due to the established clinical efficacy and safety of FTY720, we hypothesized that this immunomodulatory compound could potentially inhibit HIV infection.”
Their studies showed that FTY720 blocks HIV infection in human CD4+ T cells by hindering multiple steps in the HIV lifecycle. The drug reduced the density of CD4 on the surface of T cells, which inhibited viral binding and fusion. FTY720 also blocked HIV transmission between the cells, and consequently reduced detectable latent virus. The compound activated the antiviral restriction factor SAMHD1, leading to a reduction in levels of total and integrated HIV.
The results point to the potential targeting of S1P pathway with FTY720 as a novel strategy to inhibit HIV replication and reduce the latent reservoir. “… our results indicate that FTY720 may be an exciting novel therapy for HIV infection,” the team concluded. “FTY720 is already clinically approved and well-tolerated and we show that it also restricts HIV infection of CD4 T cells. As such, targeting the S1P-S1PR axis may be an alternative strategy to employ in the context of prevention as a potential microbicide; as an adjuvant to current ART strategies to reduce the seeding of the latent reservoir; or in strategies aimed toward viral reactivation and eradication of the latent reservoir.”