Immune-based Therapies in the Treatment of HIV/AIDS.

Franco Lori and Julianna Lisziewicz. Research Institute for Genetic and Human Therapy (RIGHT) at Policlinico S. Matteo, Pavia (Italy), and Washington, DC (USA)

Background: Antiretroviral drugs are the cornerstone of HIV therapy, however, they do not represent the ultimate treatment solution. Drawbacks of conventional drugs include important side effects, lack of improvement of HIV specific immune responses, and little/no effects on viral reservoirs. Drugs capable of modulating the immune system and therapeutic vaccines might elicit immune responses to inhibit HIV and represent a useful complement to antiretrovirals. Material and Methods: Hydroxyurea, an immunomodulatory drug, and DermaVir, a topical therapeutic vaccine, were tested in in vitro experiments, non-human primate models, and clinical trials. Results: In the first set of experiments, hydroxyurea has been shown to act synergistically with nucleoside analogues both in vitro and in several randomized, controlled clinical trials. Hydroxyurea, unlike other antiretrovirals, was found to be mostly efficient in dendritic cells and macrophages, that might represent viral reservoirs. Hydroxyurea is also a cytostatic agent, shown to restore immunologic functions, including HIV-specific T helper and CTL responses, and CD3-zeta expression. However, the perceived risk of increased toxicity has limited its development and utilization. Recently, we have unexpectedly shown that hydroxyurea was most efficacious at a lower dosage (600 mg daily) in a human dose/regimen and safety clinical trial (RIGHT 702). The consistent in vitro and in vivo findings that reducing the dosage of hydroxyurea also significantly decreases toxicity are very encouraging, and will draw renewed attention to the use of hydroxyurea as an attractive option for HIV infected patients.

In the second set of experiments, application of the therapeutic vaccine DermaVir to the surface of the skin of mice and macaques resulted in transduction of Langerhans cells, migration of these cells into lymph nodes, gene expression by genetically-modified dendritic cells, and induction of vigorous, virus-specific T cell-mediated immune responses. In chronically SIV251-infected macaques and in macaques with late-stage disease, i.e. AIDS, DermaVir, in combination with STI, progressively reduced viral rebound to a rate comparable to that observed during STI alone during primary infection, and in most cases no viral rebound was observed. Conclusions: The results represent proof of concept that immunomodulatory drugs and/or therapeutic vaccines might be employed to affect viral reservoirs, restore the immune system, and elicit HIV-specific immune responses able to control the virus.