Existing drugs control HIV
in lab cells, but no cure yet
by Liz Highleyman
Two drugs approved for other uses can inhibit HIV replication and trigger the death of HIV-infected cells in laboratory tests, researchers reported this week. These findings suggest a potential new approach for eradicating the virus, but it will likely be years – if ever – before it can be used as part of a practical cure strategy.
Hartmut Hanauske-Abel and Michael Mathews from Rutgers New Jersey Medical School and colleagues tested two related drugs, ciclopirox and deferiprone, in human embryonic stem cell cultures and in peripheral blood mononuclear cells (PBMCs) infected with HIV obtained from two patients.
Ciclopirox is an ingredient in various products used to treat fungal infections such as athlete's foot and vaginal yeast infection. Deferiprone (brand name Ferriprox) is an oral chelating agent used to manage iron overload in people with beta thalassemia, a genetic condition that causes reduced hemoglobin production.
For more than a decade Hanauske-Abel's team has been studying a novel strategy for blocking HIV replication and its detrimental effects. Their latest findings, published September 23 in the online journal PLoS ONE, explain how this multi-pronged approach works and how it might one day contribute to viral eradication in people with HIV.
The researchers found that both ciclopirox and deferiprone interfere with HIV in multiple ways. First, the drugs blocked HIV gene expression by DNA fragmentation, preventing production of new virus. In the stem cell cultures, ciclopirox and deferiprone decreased HIV expression by 40 to 50 percent.
In acutely infected PBMCs, ciclopirox completely suppressed establishment of productive infection. In PBMCs with already established infection, adding the drug reduced viral levels to undetectable. Viral breakthrough did not occur during 30 days of treatment. Even 12 weeks after stopping the drug, viral replication did not restart, suggesting that the reservoir of latent HIV was eliminated, according to the researchers.
Second, the drugs disrupted HIV's control over apoptosis, or cell suicide. Normally cells infected with viruses undergo programmed cell death, but HIV neutralizes this natural defense mechanism. This allows activated T-cells to continue producing infectious virus and enables establishment of a reservoir of HIV genetic material in long-lived inactive cells. Existing antiretroviral drugs can block HIV replication but cannot reach this hidden latent virus, which is why HIV is so hard to eradicate and why people must stay on antiretroviral treatment for life.
Ciclopirox and deferiprone restored the normal cell suicide response in HIV-infected cells by altering the function of mitochondria, or energy-producing structures within cells – a mechanism the researchers dubbed "therapeutic reclamation of apoptotic proficiency," or TRAP. In the stem cell cultures, cell survival decreased by about two-fold at 24 hours and by about five-fold at 48 hours after drug treatment. In PBMCs, 72 percent of HIV-exposed cells treated with ciclopirox underwent apoptosis.
Healthy uninfected cells, however, were minimally affected. The researchers tested 1 percent ciclopirox cream in vaginal tissue in mice, and saw no damage at concentrations high enough to suppress HIV.
"These drugs can block virus production and seem to cause the infected cells to self-destruct," HIV cure expert Sharon Lewin from Monash University in Melbourne told the Bay Area Reporter . "Drugs that don't just 'shock' but also 'kill' latently infected cells are what the field is currently searching for, so these drugs could be promising, but there's plenty more work to do."
Co-author Deepti Saxena and colleagues have already performed a proof-of-concept Phase 1 clinical trial of deferiprone in a small number of people with HIV in South Africa. Findings have not yet been published, but according to the PLoS ONE article, a one-week course of deferiprone reduced HIV viral load as much as AZT, and the effect persisted for seven weeks of post-treatment follow-up.
The next step, the researchers proposed, could be testing the drugs' antiretroviral activity in HIV-positive people who are taking them for their approved indications. Up to one-quarter of people with beta thalassemia in resource-limited countries are infected with HIV, they noted.
Three of the co-authors work for ApoPharma, which is developing deferiprone as an HIV therapy. Rutgers, Cornell University, and the National Institutes of Health have one patent for this approach and four more are pending.
"The team has uncovered a novel therapeutic approach which has promise," Dr. Steven Deeks from UCSF told the B.A.R. "The approach will unlikely work alone, however, and it will likely take years to determine if this work might one day contribute to a cure."