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Neurovirol."],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mixed glia are infiltrated with HIV-1 virus early in the course of infection leading to the development of a persistent viral reservoir in the central nervous system. Modification of the HIV-1 genome using gene editing techniques, including CRISPR\/Cas9, has shown great promise towards eliminating HIV-1 viral reservoirs; whether these techniques are capable of removing HIV-1 viral proteins from mixed glia, however, has not been systematically evaluated. Herein, the efficacy of adeno-associated virus 9 (AAV9)-CRISPR\/Cas9 gene editing for eliminating HIV-1 messenger RNA (mRNA) from cortical mixed glia was evaluated in vitro and in vivo. In vitro, a within-subjects experimental design was utilized to treat mixed glia isolated from neonatal HIV-1 transgenic (Tg) rats with varying doses (0, 0.9, 1.8, 2.7, 3.6, 4.5, or 5.4 \u00b5L corresponding to a physical titer of 0, 4.23\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    , 8.46\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    , 1.269\u2009\u00d7\u200910\n                    <jats:sup>10<\/jats:sup>\n                    , 1.692\u2009\u00d7\u200910\n                    <jats:sup>10<\/jats:sup>\n                    , 2.115\u2009\u00d7\u200910\n                    <jats:sup>10<\/jats:sup>\n                    , and 2.538\u2009\u00d7\u200910\n                    <jats:sup>10<\/jats:sup>\n                    gc\/\u00b5L) of CRISPR\/Cas9 for 72\u00a0h. Dose-dependent decreases in the number of HIV-1 mRNA, quantified using an innovative in situ hybridization technique, were observed in a subset (i.e.,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095 out of 8) of primary mixed glia. In vivo, HIV-1 Tg rats were retro-orbitally inoculated with CRISPR\/Cas9 for two weeks, whereby treatment resulted in profound excision (i.e., approximately 53.2%) of HIV-1 mRNA from the medial prefrontal cortex. Given incomplete excision of the HIV-1 viral genome, the clinical relevance of HIV-1 mRNA knockdown for eliminating neurocognitive impairments was evaluated via examination of temporal processing, a putative neurobehavioral mechanism underlying HIV-1-associated neurocognitive disorders (HAND). Indeed, treatment with CRISPR\/Cas9 protractedly, albeit not permanently, restored the developmental trajectory of temporal processing. Proof-of-concept studies, therefore, support the susceptibility of mixed glia to gene editing and the potential of CRISPR\/Cas9 to serve as a novel therapeutic strategy for HAND, even in the absence of full viral eradication.\n                  <\/jats:p>","DOI":"10.1007\/s13365-024-01193-z","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T14:02:28Z","timestamp":1707919348000},"page":"71-85","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HIV-1 mRNA knockdown with CRISPR\/CAS9 enhances neurocognitive function"],"prefix":"10.1007","volume":"30","author":[{"given":"Kristen A.","family":"McLaurin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamel","family":"Khalili","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles F.","family":"Mactutus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosemarie M.","family":"Booze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,14]]},"reference":[{"key":"1193_CR1","doi-asserted-by":"publisher","first-page":"e105256","DOI":"10.1371\/journal.pone.0105256","volume":"9","author":"SJ Abbondanzo","year":"2014","unstructured":"Abbondanzo SJ, Chang SL (2014) HIV-1 transgenic rats display alterations in immunophenotype and cellular responses associated with aging. 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