title: Efficacy of Tat-conjugated ritonavir-loaded nanoparticles in reducing HIV-1 replication in monocyte-derived macrophages and cytocompatibility with macrophages and human neurons.
abstract: Human immunodeficiency virus (HIV)-1 targets mononuclear phagocytes (MP), which disseminate infection to organs such as brain, spleen and lymph. Thus MP, which include microglia, tissue macrophages and infiltrating monocyte-derived macrophages (MDM), are important target of anti-HIV-1 drug therapy. Most of the currently used antiretroviral drugs are effective in reducing viral loadin the periphery but cannot effectively eradicate infection from tissue reservoirs such as brain MP. HIV-1 infection of the central nervous system can lead to a wide variety of HIV-1-associated neurocognitive disorders. In this study, we demonstrate that ritonavir-loaded nanoparticles (RNPs) are effective in inhibiting HIV-1 infection of MDM. Reduced infection is observed in multiple read-out systems including reduction of cytopathic effects, HIV-1 p24 protein secretion and production of progeny virions. Furthermore, the RNPs retained antiretroviral efficacy after being removed from MDM cultures. As HIV-1-infected cells in the brain are likely to survive for a long period of time, both acute and chronic infection paradigms were evaluated. Tat-peptide-conjugated RNPs (Tat-RNP) were effective in both short-term and long-term HIV-1-infected MDM. Importantly, we confirm that delivery of RNPs, both with and without Tat-peptide conjugation, is toxic neither to MDM nor to neural cells, which may be bystander targets of the nanoformulations. In conclusion, Tat-NPs could be a safe and effective way of delivering anti-HIV-1 drugs for controlling viral replication occurring within brain MP.
authors.affiliation: Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, 76107, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Borgmann
authors.forename: Kavitha S
authors.initials: KS
authors.lastname: Rao
authors.forename: Vinod
authors.initials: V
authors.lastname: Labhasetwar
authors.forename: Anuja
authors.initials: A
authors.lastname: Ghorpade
mesh_terms: D001921:Brain / Q000473:pathology / Q000821:virology; D002470:Cell Survival; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D004339:Drug Compounding / Q000379:methods; D005260:Female; D005333:Fetus; D015696:Gene Products, tat / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000178:diet therapy* / Q000473:pathology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D053758:Nanoparticles / Q000737:chemistry; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D010316:Particle Size; D011247:Pregnancy; D061251:Primary Cell Culture; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology*; D014771:Virion / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D003432:Cross-Linking Reagents; D004337:Drug Carriers; D015696:Gene Products, tat; D017320:HIV Protease Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D019438:Ritonavir