ST106 Macrophage targeted therapy for AIDS

Abstract

Background: HIV associated neurocognitive disease (HAND) involves ongoing migration of blood associated monocytes into areas of disease. The migrant CD163 expressing macrophages implicated in HAND have recently been implicated in HIV associated atherosclerosis a growing problem in HIV infected patients including those with HAND. We describe a novel approach to AIDS related macrophage diseases using PA300 (MGBG; methylglyoxal bis(guanylhydrazone) dihydrochloride monohydrate), a formulated oral polyamine biosynthesis regulator (Pathologica, LLC, Burlingame CA). Methods: PA300 was evaluated for dose dependent responses in a) in vitro macrophage culture systems and b) a rhesus model of SIV encephalopathy. Results: PA300 blocked induction of monocyte differentiation into polarized macrophages, blocked HIV infection of macrophages and killed exposed HIV infected macrophages in vitro. (ED80: 0.3-1uM). Eight rhesus macaques were SIV-infected and CD8+ T lymphocyte depleted. At 21 days post-infection, a time when CNS disease would be apparent, animals were given PA300 (3mg/kg; n=2, 10mg/kg; n=2; 30mg/kg; n=2) or vehicle control (n=2). After one month of treatment: No evidence for CNS infection, macrophage infiltration or brain pathology was observed at the highest dose with intermediate efficacy at lower doses. SIV associated myocarditis was also reversed. Blood CD14+ cells showed no detectible SIV DNA at intermediate and high doses of PA300. Summary: PA300 is a novel macrophage differentiation regulator with additional activity against HIV infected macrophages. Treatment of macaques with SIV associated encephalopathy and myocarditis resulted in disease reversal and loss of infected macrophages in the brain and blood.