Tipranavir exhibits different effects on opportunistic pathogenic fungi

Abstract

Tipranavir (TPV) is a non-peptidic protease inhibitor (PI) that represents one of the latest options approved in the salvage setting for HIV-infected multi-drug resistant patients. In this study, we explored whether TPV affects virulence of opportunistic fungi such as Cryptococcus neoformans and Candida albicans. C. neoformans and C. albicans were cocultured in the presence or absence of TPV for various time periods. Subsequently, growth inhibition, phospholipases, proteases and capsule size were examined. In selected in vivo experiments, TPV was administered in immunocompetent and immunosuppressed mice. Survival rate and colony forming units from organs were evaluated in mice systemically challenged with C. neoformans or C. albicans. Indeed, when cultured in the presence of TPV, both fungi showed significant reduction in protease and phospholipase production, but TPV showed an opposite effect on the major virulence factors of C. neoformans and C. albicans by inhibiting capsule while promoting mycelial transition, respectively. TPV impaired in vitro growth of C. neoformans, but not of C. albicans. Moreover, TPV-treated C. neoformans, but not C. albicans, resulted more susceptible to killing by human neutrophils. Finally, TPV showed a therapeutic effect in experimental systemic cryptococcosis, as evaluated by reduced fungal burden in brain and liver of immunocompetent and immunodepressed mice. These new data indicate that TPV could act in multiple ways by diversifying its effects on various opportunistic pathogenic fungi.