Hydroxyurea: in vitro evidence of potency against HIV viral reservoirs

Dendritic cells (DCs), which take up antigen and display it to the immune system, are found in the skin, joints and circulating blood as well as in lymphoid tissue. HIV is able to infect a number of different types of immune system cells, and there is mounting evidence that DCs play an important role in the disease.

Along with macrophages, DCs are now thought to be responsible for spreading the initial HIV infection, despite HIV replication occurring at only very low levels in these cells. DCs are also thought to act as a long-term reservoir of the virus. Failure to eradicate sequestered virus can result in a rebound of infection, and archiving of resistant mutant viruses in such reservoirs negates re-use of a drug that has previously failed, even after a prolonged treatment holiday.

The treatment options for HIV-positive individuals include a range of different drugs, and previous work has established that cells of the immune system are differentially susceptible to these agents. In vitro analysis carried out by Giampiero Piccinini, and published in the Journal of Virology this month, was designed to compare the antiretroviral activity of different agents in dendritic cells and T lymphocytes.

Cells were cultured in the presence of either hydroxyurea, a chemical that reduces the availability of dNTPs that are required for viral DNA replication, or one of two inhibitors of the HIV protease enzyme, ritonavir and indinavir. The drugs were administered at therapeutic concentrations. The study found evidence that HIV was released at a low level by DC cultures, measured by recording the level of a viral protein, p24. However, when incubated with hydroxyurea or indinavir viral release from DCs was potently inhibited.

The antiretroviral activity of these agents, and that of ritonavir, was then compared in parallel experiments, in DCs and lymphocytes. The protease inhibitors were found to completely inhibit HIV release in lymphocytes, but not in DCs, at the maximum drug concentration used. In contrast, clinically relevant concentrations of hydroxyurea were found to significantly inhibit release of the virus in DC but not T lymphocyte cells.

Control experiments accounted for any effects of drug toxicity on the cells, and found that the agents did not induce maturation of the DCs, a phenomenon known to affect virus release.

Finally, the ability of the agents to prevent the spread of HIV from DCs to lymphocytes was gauged. In the absence of drugs, the amount of viral antigen released into mixed cultures of HIV-infected DCs and uninfected lymphocytes increased as a result of lymphocyte infection and consequent viral replication. In the presence of hydroxyurea, release of HIV was strongly inhibited. Since the previous experiments had shown no effect of hydroxyurea on T lymphocytes, the authors conclude that the agent potently suppressed the transmission of HIV from DCs.

These results suggest that a drug that selectively targets HIV in viral reservoirs may be an important addition to a successful antiretroviral regimen. Clinical trials to determine the toxicity profile of new combinations are needed before studies can be carried out to assess the clinical relevance of these findings.