A simple anti-fungal cream kills off HIV in the Petri dish, leaving no viral traces as today’s HIV drugs do, researchers say.
If it works in HIV patients, huge financial and timing hurdles could be cleared, as the drug, ciclopirox, is already FDA-approved (for topical treatment of athlete’s foot and vaginal yeast infections), says a Rutgers New Jersey Medical School team publishing a recent PLOS One paper on the subject. The approach may also prove effective against many virus-resistant diseases, from malaria to tuberculosis.
“Response has been tremendous,” says co-author Harmut Hanauske-Abel.
Pioneering HIV co-discoverer Robert Gallo, head of the University of Maryland’s Institute of Human Virology, is wary. He tells Drug Discovery & Development he believes ciclopirox may work topically as a prophylactic, but not systemically as a drug targeting established HIV. “From their writing, it looks like it could be used as a prophylactic microbicide, yes,” he says. “But I haven’t seen any results where they isolate the active compound and show it can be used systemically.”
Hanauske-Abel says his team’s preclinical work, added to other studies, indicates topical ciclopirox may work systemically, both pre-and-post infection. He notes a University of Toronto group isolated the active compound in ciclopirox and reported at a conference they used it, with some success, against acute myeloid leukemia (AML). He says a similar drug, approved for systemic use—deferiprone (for beta thalassemia)—works against HIV both in vitro (as the PLOS paper shows), and in vivo. (The latter is according to an as-yet unpublished African HIV trial cited in the PLOS paper).
In mice, Hanauske-Abel adds, ciclopirox was found by a Louisiana State University group to make breast, colon and rhabdomyosarcoma tumors “selectively melt away, leaving healthy cells untouched.”
“We see similar things,” he says. “It is unheard of to selectively kill HIV-infected cells. But we do it, by destroying the factories in which the virus is growing. The current anti-retrovirals let these factories persist.”
Says co-author Mathews, chairman of the school’s biochemistry and molecular medicine department: “In PLOS ONE, we show that deferiprone has the same action as ciclopirox on HIV-infected cells. This backs up biochemical studies in our earlier paper in Retrovirology, and supports our idea these drugs can target HIV-infected cells, rather than just the elusive virus, and eradicate them after infection has occurred.”
All told, says Hanauske-Abel, the approach may offer hope that a cure for HIV may be no farther away than the local pharmacy. The team wants to launch a ciclopirox/HIV clinical trial with the above AML group.
The way it all seems to work: Ciclopirox and deferiprone can cause tumor cells, and HIV-infected cells, to commit suicide (or undergo “apoptosis”). Healthy cells normally commit apoptosis when infected. HIV keeps its host CD4 cells alive by blocking that apoptosis, and co-opting the cells’ DNA machinery.
Patients can live with HIV for decades on today’s antiretroviral drugs. But these must be taken for a lifetime. They never fully eradicate HIV, just prompt it to hide in latent form. Over time, drug-resistance often occurs.
Hanauske-Abel and Mathews showed that ciclopirox and deferiprone both inhibit a cellular protein called deoxyhypusine hydroxylate (DOHH) in CD4 positive cells, which seems to slow their replication. “It has long been established that DOHH inhibition can arrest cell proliferation, which is required for maximal production of HIV,” says Hanauske-Abel. “And cell proliferation-slowing drugs like hydroxyurea (similar in structure to ciclopirox) are known to hold back viral production without causing immune deficiency. DOHH inhibition may similarly score a first hit against the virus.”
DOHH inhibition then leads to decreased HIV-1 transcription, which in turn releases virally suppressed apoptosis in HIV-infected cells. (In non-infected cells, DOHH inhibition simply reduces the apoptotic threshold, which does no damage.) HIV-infected cells die; healthy cells don’t. The virus does not reappear, even weeks after drug removal.
Mathews says the researchers envision that inhibiting HIV transcription, “lifts the virus-imposed suppression of the cellular apoptotic response.”
Hanauske-Abel believes this sleight of hand has been overlooked because apoptosis alarms HIV researchers. “They thought enhancing apoptosis would enhance dismemberment of the immune system.” But the two drugs induce apoptosis only in infected cells. “So now we say, ‘Consider apoptosis as a weapon against HIV,’” he says.
Ironically, Gallo was one of the first to unearth the mechanism-- in HIV-infected cells-- in what Hanauske-Abel calls a “spectacular” 1994 Science paper on the similar, aforementioned hydroxyurea, which depleted HIV DNA in infected cells in vitro. As viral DNA is entwined in cellular DNA, the infected cells may also have been killed. The field did not pursue it.
Says Mathews: “To my knowledge no one else has advanced the idea [that] apoptosis be harnessed to eliminate infected cells. We can be pretty sure of this because of the stiff opposition we experienced during the review process at other journals.”
And the approach may work against many drug-resistant viruses, as many viruses disable apoptosis, says Hanauske-Abel. “The induction of cell death is what we humans do each day to get rid of cancer cells. The PLOS paper suggests we change dogma” to apply this elegant approach to HIV.