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The topical anti-fungal agent ciclopirox causes HIV-infected cells to commit suicide by jamming up the cells’ powerhouse, the mitochondria, according to a recent study.The study, published in PLoS One, found that unlike currently available anti-HIV drugs, ciclopirox eradicates infectious HIV from cell cultures, with no rebound of virus when the drug is stopped.
The topical anti-fungal agent ciclopirox causes HIV-infected cells to commit suicide by jamming up the cells’ powerhouse, the mitochondria, according to a recent study.
The study, published in PLoS One, found that unlike currently available anti-HIV drugs, ciclopirox eradicates infectious HIV from cell cultures, with no rebound of virus when the drug is stopped.
Researchers at Rutgers New Jersey Medical School, demonstrated that ciclopirox and deferiprone inhibit a cellular protein hydroxylase-DOHH-in CD4 positive cells.
“It had long been established that DOHH inhibition can arrest cell proliferation, required for maximal production of HIV, and cell proliferation-slowing drugs like hydroxyurea are known to hold back viral production without causing immune deficiency,” said researcher Hanauske-Abel, MD.
“DOHH inhibition may similarly score a first hit against the virus, but this is just a minor pinch compared to what happens next: All HIV infected cells that contain the genome of HIV and have been hijacked by HIV to produce infective HIV offspring by the billions per day, just shut down their production and burn up the HIV genome inside of them by committing suicide.
“HIV-infected cells rather kill themselves than be used by the virus to infect the entire body, a process appropriately labeled ‘altruistic suicide,’ or ‘apoptosis’ in scientific terms (accordingly, the researchers named this “therapeutic reclamation of apoptosis” or TRAP),” Dr Hanauske-Abel said.
When the DOHH inhibitors ciclopirox or deferiprone are then removed from the once highly infectious cultures, these cultures now are no longer infectious and new CD4 positive cells can be injected into them without restarting a new round of infection, he said.
“After monotherapy with either DOHH inhibitor, the cultures behave as if HIV has left without the ability to come back, ever; its DNA is so destroyed that it can no longer reignite infection.”
This is a preclinical study. The researchers conducted a phase 1 trial with deferiprone and are in the process of completing the manuscript of that clinical study.
“As a physician, any phase 1 study is not immediately relevant for managed care and hospital decision-makers - except to put that item on their radar screen,” Dr Hanauske-Abel said. “Any drug that has the potential to terminate HIV infection, or shut it down for some time until internal re-infection might occur from some hidden sanctuary in latently infected cells-a specialty of HIV that we did not yet examine-has obviously enormous economic significance in terms of reducing cost of treatment.
“At the present time, billions of dollars are required just for the day-to-day supply of antiretrovirals that do not eliminate the productions sites of HIV even when used in combination therapy like combination antiretroviral therapy (cART/highly active antiretroviral therapy [HAART]). Deferiprone and ciclopirox do eliminate the productions sites of HIV when use in monotherapy.”
The availability of about 2 dozen suppressive antiretrovirals create the public impression that HIV-AIDS is manageable and that humans have controlled the HIV-AIDS pandemic. Not so, according to Dr Hanauske-Abel.
“Suppressive antiretrovirals are available to at most 50 percent of all infected persons, and to as few as 12 percent or less in resource-limited hyperepidemic countries,” he said.
“The need for life-long cART extracts extraordinary economic expense. In the absence of protective microbicides and effective vaccines, efforts to treat patients and slow the pandemic are locked into expanded use of suppressive antiretrovirals, a ‘more of the same’ strategy.
“These drugs do not attack the sites that, by mass-producing HIV-1, enable the selection of genetic variants for enhanced drug resistance and human infectivity: cART leaves infected cells intact, ready to launch HIV-1 resistance and breakthrough, and to drive rebound as soon as medicinal suppression wanes. Escape mutations are transmitted and propagate drug-experienced virus to drug-naive persons. Despite cART, HIV-1 reportedly gained in virulence,” Dr Hanauske-Abel said.
“As with drug-resistant TB and drug-resistant malaria and drug-resistant E coli and drug-resistant S aureus, we are not only facing fiscal limits for treatment by drugs, we are facing the exhaustion of the chemical library of basic structures that can be modified to catch escape mutations,” Dr Hanauske-Abel said. “We can modify the penicillin or cephalosporin core not endlessly, but the microbes can mutate way endlessly, they have Darwin and evolution on their side. With regard to HIV, we therefore pursued to idea to destroy its production sites selectively: If virus cannot be produced, then there are no mutants that can be selected for drug resistance. Darwin and evolution no longer are in the employ of HIV. And selective killing of pathogenic cells is a basic therapeutic principle, done every day in medical oncology.”