Acne drug prevents HIV activation from latently infected cells

A safe and inexpensive antibiotic in use since the 1970s for treating acne effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and producing virus, scientists from Johns Hopkins University report in the Journal of Infectious Diseases this week.

Unlike the drugs currently used in antiretroviral treatment which target the virus, minocycline homes in on, and adjusts, CD4 T-cells, the primary targets of HIV infection. Minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and infection of further CD4 cells.

Minocycline may have the potential to limit HIV replication from the pool of latently infected CD4 cells believed to constitute the major source of ongoing viral replication in patients with viral load below the limits of detection on current tests.

Even in individuals with a viral load below 50 copies/ml, the limit of detection of most current assays, low-level viral replication is still detectable using more sensitive research tools, and occasional spikes, or 'blips' in viral load may occur, driving viral load briefly above the limits of detection.

These blips, and the low-level replication that persists even in people treated for years with HAART, appear to be generated by the activation of latently infected CD4 cells, which pump out virus for a few hours and set off another round of infection – including the 're-seeding' of more cells to join the reservoir of latently infected cells.

Any interruption of HAART leads to a rapid rebound in viral load, indicating that activation of even a small number of latently infected cells is sufficient to trigger a massive resurgence of virus levels in the absence of antiretroviral drugs.

Current efforts to cure HIV infection focus on activating this pool of latently infected cells in order to rid the body of the virus, but the Johns Hopkins research suggests another possibility: after driving down viral load with antiretroviral drugs, the virus might be kept in long-term hibernation by a drug or combination of drugs which block the activation process.

For the time being the researchers are suggesting that minocycline should be explored as an adjunct to antiretroviral therapy, due to the low likelihood that the virus could develop resistance to it.

“The powerful advantage to using minocycline is that the virus appears less able to develop drug resistance because minocycline targets cellular pathways not viral proteins,” said Janice Clements, professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

The drug might also reduce inflammation that persists in HAART-treated patients, and prevent migration of the virus into the central nervous system, the researchers argue. Indeed, minocycline is already being tested as a treatment for cognitive impairment in people with HIV in the United States and Uganda.

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells.

The Hopkins group connected the dots between that study and previous research of their own showing that minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T-cell activation and proliferation.

“Since minocycline reduced T cell activation, you might think it would have impaired the immune systems in the macaques, which are very similar to humans, but we didn’t see any deleterious effect,” says Gregory Szeto, a graduate student in the Department of Cellular and Molecular Medicine working in the Retrovirus Laboratory at Hopkins.

“This drug strikes a good balance and is ideal for HIV because it targets very specific aspects of immune activation.”

The success with the animal model prompted the team to study in test tubes whether minocycline treatment affected latency in human T-cells infected with HIV. Using cells from HIV-infected humans on HAART, the team isolated the 'resting' immune cells and treated half of them with minocycline. Then they counted how many virus particles were reactivated, finding completely undetectable levels in the treated cells versus detectable levels in the untreated cells.

“Minocycline reduces the capability of the virus to emerge from resting infected T cells,” Szeto explains. “It prevents the virus from escaping in the one in a million cells in which it lays dormant in a person on HAART, and since it prevents virus activation it should maintain the level of viral latency or even lower it. That’s the goal: Sustaining a latent non-infectious state.”

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T-cell activation.

However, the antibiotic doesn’t completely obliterate T-cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV.

“HIV requires T cell activation for efficient replication and reactivation of latent virus,” Clement says, “so our new understanding about minocyline’s effects on a T cell could help us to find even more drugs that target its signaling pathways.”

An accompanying commentary by Karen Copeland and James Brooks of Canada’s National HIV and Retrovirology Laboratories highlights a number of uncertainties about use of the drug.

The dose used in the test-tube experiments in this study resulted in much higher drug concentrations than those usually achieved with oral dosing of the drug, and this may account for the effect.

The interaction of minocycline with antiretrovirals is unclear (it is known to reduce atazanavir levels, for example).

Adapted from a Johns Hopkins University press release.