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: Kathleen Borgmann, Kavitha S Rao, Vinod Labhasetwar, Anuja Ghorpade
• Journal: AIDS research and human retroviruses (AIDS Res Hum Retroviruses) Vol. 27 Issue 8 Pg. 853-62 (Aug 2011) ISSN: 1931-8405 [Electronic] United States
• PMID: 21175357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cross-Linking Reagents
• Drug Carriers
• Gene Products, tat
• HIV Protease Inhibitors
• reverse transcriptase, Human immunodeficiency virus 1
• HIV Reverse Transcriptase
• Ritonavir

Topics

• Brain (pathology, virology)
• Cell Survival
• Cells, Cultured
• Cross-Linking Reagents (chemistry)
• Drug Carriers (chemistry, pharmacology)
• Drug Compounding (methods)
• Female
• Fetus
• Gene Products, tat (chemistry, pharmacology)
• HIV Infections (diet therapy, pathology, virology)
• HIV Protease Inhibitors (chemistry, pharmacology)
• HIV Reverse Transcriptase (metabolism)
• HIV-1 (enzymology)
• Humans
• Macrophages (drug effects, metabolism, virology)
• Nanoparticles (chemistry)
• Neurons (drug effects, metabolism, virology)
• Particle Size
• Pregnancy
• Primary Cell Culture
• Ritonavir (chemistry, pharmacology)
• Virion (drug effects)
• Virus Replication (drug effects)