Appropriate Time to Start Antiretroviral Therapy in HIV-infected Patients with Penicilliosis marneffei

Thongchai Utkham, Parichat Salee, Khuanchai Supparatpinyo
2017 Open Forum Infectious Diseases  
Background. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) still affect 40-70% of HIV-infected people. The pathogenesis of HAND is multi-factorial and poorly understood. Macroautophagy is a cellular self-digestion process with essential roles in defense against infection, aging, and neurodegeneration. While there are a few studies showing a link between aberrant macroautophagy and cognitive defects in HIV infection, little is known of how HIV or
more » ... HIV or antiretrovirals impact macroautophagy in cells of the CNS. We studied autophagy in macrophages and astrocytes-two major CNS cell types involved in HAND pathogenesis-after treatment with HIV Nef or common ART components to characterize further the pathogenesis of HAND. Methods. PBMC were cultured to generate monocyte-derived macrophages (MDM). MDM were treated 24 or 48 hours with 5 ng/mL Tenofovir and/or 109 ng/mL Emtricitabine and lysates collected. Primary human astrocytes were treated 24 hours with 10 ng HIV Nef or 5 ng/mL Tenofovir + 109 ng/mL emtricitabine + 14 ng/mL raltegravir (ART) and lysates collected. Lysates were analyzed by western blot for LC3-II and p62 (autophagy markers) using Image Studio. Results. LC3-II levels increased 1.5-, 1.6-, and 1.7-fold in MDM treated 24 hours with Tenofovir, Emtricitabine or Truvada, respectively, and p62 level decreased 25% after 24h Truvada, relative to untreated MDM. After 48 hours Truvada, LC3-II and p62 levels decreased 30% relative to control MDM. This indicates an initial upregulation followed by rapid downregulation of autophagy in antiretroviral-treated MDM. In astrocytes treated with Nef, LC3-II, and p62 flux (degradation) increased 3-fold and 1.7-fold, respectively, indicating abnormal enhancement of autophagy. Interestingly, while ART treatment increased LC3-II flux 3-fold, p62 degradation decreased 50% relative to controls, signifying a change in autophagy that impacts LC3-II and p62 differently.
doi:10.1093/ofid/ofx163.408 fatcat:coq4t4h6nbgobcxxvcqrwqscs4