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      The Paradox of HIV Blood–Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies

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          Abstract

          HIV attacks the body’s immune cells, frequently compromises the integrity of the blood–brain barrier (BBB), and infects the CNS in the early stages of infection. Dysfunction of the BBB further potentiates viral replication within the CNS, which can lead to HIV-associated neuropathology. Antiretroviral therapy (ART) significantly improves HIV patient outcomes and reduces mortality rates. However, there has been limited progress in targeting latent viral reservoirs within the CNS, which may eventually lead to rebound viremia. While ART drugs are shown to be effective in attenuating HIV replication in the periphery, the protection of the brain by the BBB offers an isolated sanctuary to harbor HIV and maintains chronic and persistent replication within the CNS. In this review, we elucidate the pathology of the BBB, its ability to potentiate viral replication, as well as current therapies and insufficiencies in treating HIV-infected individuals.

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          Nanoparticle-based targeted drug delivery.

          Rajesh Singh, James W. Lillard (2009)
          Nanotechnology could be defined as the technology that has allowed for the control, manipulation, study, and manufacture of structures and devices in the "nanometer" size range. These nano-sized objects, e.g., "nanoparticles", take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved solubility, and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnology for the biologist and discusses the attributes of our novel XPclad((c)) nanoparticle formulation that has shown efficacy in treating solid tumors, single dose vaccination, and oral delivery of therapeutic proteins.
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            A novel quantitative approach for measuring the reservoir of latent HIV-1 proviruses

            Katherine M. Bruner, Zheng Wang, Francesco R. Simonetti … (2019)
            A stable latent reservoir for HIV-1 in resting CD4+ T-cells precludes cure 1–3 . Curative strategies targeting the reservoir are being tested 4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays (QVOAs) for cells releasing infectious virus following one round of T-cell activation 1 . However, QVOAs and newer assays for cells producing viral RNA after activation 6 may underestimate reservoir size because one round of activation does not induce all proviruses 7 . Many studies rely on simple PCR-based assays to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority proviruses are defective 7–9 . We describe a novel approach that separately quantifies intact and defective proviruses and show that the dynamics of cells carrying intact and defective proviruses are different in vitro and in vivo, a finding with implications for targeting the intact proviruses that are a barrier to cure.
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              Blood-brain barrier active efflux transporters: ATP-binding cassette gene family.

              Wolfgang Löscher, Heidrun Potschka (2004)
              The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 7808616
                Journal ID (pubmed-jr-id): 7840
                Journal ID (nlm-ta): Trends Neurosci
                Journal ID (iso-abbrev): Trends Neurosci.
                Title: Trends in neurosciences
                ISSN (Print): 0166-2236
                ISSN (Electronic): 1878-108X
                Publication date Nihms-submitted: 29 June 2020
                Publication date (Electronic): 15 July 2020
                Publication date (Print): September 2020
                Publication date PMC-release: 11 September 2020
                Volume: 43
                Issue: 9
                Pages: 695-708
                Affiliations
                [1 ]University of Miami Miller School of Medicine, Department of Biochemistry and Molecular Biology, Miami, FL, USA
                [2 ]Dr JT Macdonald Foundation Biomedical Nanotechnology Institute of the University of Miami, Miami, FL, USA
                [3 ]Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
                [4 ]University of Miami Clinical and Translational Science Institute, Miami, FL, USA
                Author notes
                [* ]Correspondence: mtoborek@ 123456med.miami.edu (M. Toborek).
                Article
                Manuscript ID: NIHMS1607549
                DOI: 10.1016/j.tins.2020.06.007
                PMC ID: 7483662
                PubMed ID: 32682564
                SO-VID: 34fd5b1e-923a-47be-b501-d4e253ebe7ed
                License:

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                ScienceOpen disciplines: Neurosciences
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                ScienceOpen disciplines: Neurosciences

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