Next Article in Journal
Hepatitis B Virus-X Downregulates Expression of Selenium Binding Protein 1
Next Article in Special Issue
A High-Throughput HIV-1 Drug Screening Platform, Based on Lentiviral Vectors and Compatible with Biosafety Level-1
Previous Article in Journal
The gp44 Ejection Protein of Staphylococcus aureus Bacteriophage 80α Binds to the Ends of the Genome and Protects It from Degradation
Previous Article in Special Issue
Differences in HIV Markers between Infected Individuals Treated with Different ART Regimens: Implications for the Persistence of Viral Reservoirs
Open AccessArticle

An Elvitegravir Nanoformulation Crosses the Blood–Brain Barrier and Suppresses HIV-1 Replication in Microglia

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Plough Center for Sterile Drug Delivery Solutions, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Department of Pharmacology & Experimental Neuroscience, University Nebraska Medical Center, Omaha, NE 68198, USA
Department of Immunology and Microbiology, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
Authors to whom correspondence should be addressed.
Viruses 2020, 12(5), 564;
Received: 21 April 2020 / Revised: 16 May 2020 / Accepted: 18 May 2020 / Published: 20 May 2020
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
Even with an efficient combination of antiretroviral therapy (ART), which significantly decreases viral load in human immunodeficiency virus type 1 (HIV-1)-positive individuals, the occurrence of HIV-1-associated neurocognitive disorders (HAND) still exists. Microglia have been shown to have a significant role in HIV-1 replication in the brain and in subsequent HAND pathogenesis. However, due to the limited ability of ART drugs to cross the blood–brain barrier (BBB) after systemic administration, in addition to efflux transporter expression on microglia, the efficacy of ART drugs for viral suppression in microglia is suboptimal. Previously, we developed novel poly (lactic-co-glycolic acid) (PLGA)-based elvitegravir nanoparticles (PLGA-EVG NPs), which showed improved BBB penetration in vitro and improved viral suppression in HIV-1-infected primary macrophages, after crossing an in vitro BBB model. Our objective in the current study was to evaluate the efficacy of our PLGA-EVG NPs in an important central nervous system (CNS) HIV-1 reservoir, i.e., microglia. In this study, we evaluated the cyto-compatibility of the PLGA-EVG NPs in microglia, using an XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and cellular morphology observation. We also studied the endocytosis pathway and the subcellular localization of PLGA NPs in microglia, using various endocytosis inhibitors and subcellular localization markers. We determined the ability of PLGA-EVG NPs to suppress HIV-1 replication in microglia, after crossing an in vitro BBB model. We also studied the drug levels in mouse plasma and brain tissue, using immunodeficient NOD scid gamma (NSG) mice, and performed a pilot study, to evaluate the efficacy of PLGA-EVG NPs on viral suppression in the CNS, using an HIV-1 encephalitic (HIVE) mouse model. From our results, the PLGA-EVG NPs showed ~100% biocompatibility with microglia, as compared to control cells. The internalization of PLGA NPs in microglia occurred through caveolae-/clathrin-mediated endocytosis. PLGA NPs can also escape from endo-lysosomal compartments and deliver the therapeutics to cells efficiently. More importantly, the PLGA-EVG NPs were able to show ~25% more viral suppression in HIV-1-infected human-monocyte-derived microglia-like cells after crossing the in vitro BBB compared to the EVG native drug, without altering BBB integrity. PLGA-EVG NPs also showed a ~two-fold higher level in mouse brain and a trend of decreasing CNS HIV-1 viral load in HIV-1-infected mice. Overall, these results help us to create a safe and efficient drug delivery method to target HIV-1 reservoirs in the CNS, for potential clinical use. View Full-Text
Keywords: HIV; antiretroviral therapy; elvitegravir; nanomedicine; microglia HIV; antiretroviral therapy; elvitegravir; nanomedicine; microglia
Show Figures

Graphical abstract

MDPI and ACS Style

Gong, Y.; Zhi, K.; Nagesh, P.K.B.; Sinha, N.; Chowdhury, P.; Chen, H.; Gorantla, S.; Yallapu, M.M.; Kumar, S. An Elvitegravir Nanoformulation Crosses the Blood–Brain Barrier and Suppresses HIV-1 Replication in Microglia. Viruses 2020, 12, 564.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop