NOVEL TREATMENTS FOR HIV-1 RELATED PSORIASIS

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DESCRIPTION (applicant's Abstract): Psoriasis is a common and enigmatic skin disease that generally occurs in otherwise healthy individuals. However, since the AIDS epidemic, it has become clear that psoriasis is one of the cutaneous manifestations of HIV-1 infection. This phenomenon presents several dilemmas for dermatologists beyond pathophysiological issues, to include consideration of treatment alternatives. Since the majority of successful psoriatic treatments are immunosuppressive, it is a challenge to use such drugs in the setting of HIV-1. Based on these considerations, it is clear that novel therapeutic strategies are necessary to meet the clinical challenge of treating HIV-1 positive psoriasis patients. We propose to use an innovative model system that employs psoriatic plaques transplanted onto SCID mice to identify novel treatment strategies. SCID mice cannot reject the transplanted human skin, and we have validated that all measurable abnormalities examined to date between pre- and post-transplanted skin are retained in this model. Preliminary data indicate that we can effectively treat and completely resolve transplanted psoriatic plaques using intralesional cyclosporin A (CyA) analogous to earlier published studies in HIV-1 negative psoriatic patients. The main advantage of using this animal model is that no patient is directly exposed to the treatments, thereby avoiding any iatrogenic impact on the patient's immune status, or risk for combating opportunistic infections. The treatment agents we will focus on include IL-10, CsA, and retinoic acid. IL-10 was chosen because it is a type 2 cytokine that inhibits production of type 1 cytokines known to be elevated in psoriatic plaques, as well as inhibiting cell-mediated immune reactions. The effectiveness of IL-10 will be compared/contrasted to 2 other drugs that are already known to be useful in psoriasis. Furthermore, these agents have also recently been found to have antiviral effects on HIV-1, and hence may be capable of improving psoriasis with HIV-1 by both inhibiting the local immune hyperactivity in skin, as well as by blocking HIV-1 replication. All treatments will be examined for their effects on epidermal keratinocyte proliferation, immune cell activation, and HIV-1 replication. If any or all of these treatments improve transplanted psoriatic plaques, then this data would provide support for moving ahead with phase I clinical trials. It is likely that positive results using the SCID model will pave the way for accelerating production by the biotechnology industry of IL-I0 that could be administered with a dermatological formulation to human subjects, and assuring institutional review boards that a possible beneficial result would occur to balance potential risks and side effects. By devising and optimizing new therapeutic strategies using the SCID model, clinical dividends that will result for HIV-1 infected patients may also extend to psoriatic patients not infected with HIV-1.