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One major effort to purge these cells has focused on developing the \u201cshock and kill\u201d approach for forcing provirus reactivation to induce cell killing by viral cytopathic effects, host immune responses, or both. We conducted kinetic and mechanistic studies of HIV\u20101 protein expression, virion production, and cell\u2010to\u2010cell virus transmission during provirus reactivation. Provirus\u2010activated ACH\u20102 cells stimulated with romidepsin (RMD) or PMA produced Nef early, and then Env and Gag in parallel with the appearance of virions. Env on the surface of provirus\u2010activated cells and cellular F\u2010actin were critical in the formation of virological synapses to mediate cell\u2010to\u2010cell transmission of HIV\u20101 from provirus\u2010activated cells to uninfected cells. This HIV\u20101 cell\u2010to\u2010cell transmission was substantially more efficient than transmission seen via cell\u2010free virus spread and required F\u2010actin remodeling and CD4, but not chemokine receptors. Resting human primary CD4<jats:sup>+<\/jats:sup> T cells including na\u00efve and memory subpopulations and, especially the memory CD4<jats:sup>+<\/jats:sup> T cells, were highly susceptible to HIV\u20101 infection via cell\u2010to\u2010cell transmission. Cell\u2010to\u2010cell transmission of HIV\u20101 from provirus\u2010activated cells was profoundly decreased by protease inhibitors (PIs) and neutralizing antibodies (nAbs) that recognize the CD4\u2010binding site (CD4bs) such as VRC01, but not by reverse transcriptase (RT) inhibitor Emtricitabine (FTC). Therefore, our results suggest that PIs with potent blocking abilities should be used in clinical application of the \u201cshock and kill\u201d approach, most likely in combination with CD4bs nAbs, to prevent new HIV\u20101 infections.<\/jats:p>","DOI":"10.1002\/jmv.28005","type":"journal-article","created":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T01:54:50Z","timestamp":1657936490000},"page":"5434-5450","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cell\u2010to\u2010cell transmission of HIV\u20101 from provirus\u2010activated cells to resting na\u00efve and memory human primary CD4 T cells is highly efficient and requires CD4 and F\u2010actin but not chemokine receptors"],"prefix":"10.1002","volume":"94","author":[{"given":"Jie","family":"Lan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Indiana University School of Medicine Indianapolis Indiana 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