{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:23:40Z","timestamp":1785435820283,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,9]]},"group-title":"Biochemistry","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R35GM142745"],"award-info":[{"award-number":["R35GM142745"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["National Institutes of Health"],"award-info":[{"award-number":["National Institutes of Health"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21AI167693"],"award-info":[{"award-number":["R21AI167693"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Due to its ability to establish a pool of undetectable and latently infected cells that can initiate viral production through random reactivation, a cure to human immunodeficiency virus (HIV) infections has remained elusive. Many approaches have been proposed, including the \u201cshock and kill\u201d method where latency reversing agents (LRAs) are administered to reactivate latently infected cells out of latency and remove them through immune targeting and clearance, and the \u201cblock and lock\u201d method where latency promoting agents (LPAs) are administered to inhibit reactivation and potentially induce a \u201cdeep latency\u201d state where infected cells can no longer reactivate. Previous large scale drug screen studies have demonstrated a correlation between a compound\u2019s capability to modulate the fluctuations (or \u201cnoise\u201d) in HIV gene expression and its potential to modulate HIV latency. However, measurements of gene expression noise are labor-and cost-intensive. To circumvent these drawbacks, we trained a variational autoencoder (VAE) on a previously published large scale time-lapse fluorescence microscopy dataset, and performed an\n                  <jats:italic>in silico<\/jats:italic>\n                  screening of \u223c175,000 compounds for HIV latency modulators. Out of the top 113 predicted modulators that were experimentally tested, 16 latency reversing agent (LRA) synergizers and 2 latency promoting agents (LPAs) were confirmed, yielding an overall experimental hit rate of 15.9%. Our work demonstrates that\n                  <jats:italic>in silico<\/jats:italic>\n                  drug screening modalities, guided by existing large-scale experimental datasets, can yield high experimental hit rates, reducing costs incurred from labor-intensive wet lab-focused methodologies.\n                <\/jats:p>","DOI":"10.64898\/2026.07.08.737074","type":"posted-content","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:15:26Z","timestamp":1783602926000},"source":"Crossref","is-referenced-by-count":0,"title":["Variational Autoencoder-enabled High-throughput Drug Screening for HIV Latency Modulators predicted through Noise in Gene Expression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9913-0416","authenticated-orcid":false,"given":"Yiyang","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Horne","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5237-4712","authenticated-orcid":false,"given":"Xuenan","family":"Mi","sequence":"additional","affiliation":[{"name":"Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3265-3539","authenticated-orcid":false,"given":"Shivank","family":"Nag","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohom","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6006-4888","authenticated-orcid":false,"given":"Roy D.","family":"Dar","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-5381","authenticated-orcid":false,"given":"Diwakar","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"},{"name":"Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA"},{"name":"Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA"},{"name":"Department of Plant Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA"},{"name":"Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071304100885000_2026.07.08.737074v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.60.041807.123549"},{"key":"2026071304100885000_2026.07.08.737074v1.2","doi-asserted-by":"crossref","first-page":"e0162704","DOI":"10.1371\/journal.pone.0162704","article-title":"Opportunistic Infections in HIV-Infected Patients Differ Strongly in Frequencies and Spectra between Patients with Low CD4+ Cell Counts Examined Postmortem and Compensated Patients Examined Antemortem Irrespective of the HAART Era","volume":"11","year":"2016","journal-title":"PLoS ONE"},{"key":"2026071304100885000_2026.07.08.737074v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.6189183"},{"key":"2026071304100885000_2026.07.08.737074v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1256304"},{"key":"2026071304100885000_2026.07.08.737074v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254194"},{"key":"2026071304100885000_2026.07.08.737074v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nm880"},{"key":"2026071304100885000_2026.07.08.737074v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2103692118"},{"key":"2026071304100885000_2026.07.08.737074v1.8","doi-asserted-by":"crossref","first-page":"e183084","DOI":"10.1172\/jci.insight.183084","article-title":"Mechanisms and efficacy of small molecule latency-promoting agents to inhibit HIV reactivation ex vivo","volume":"9","year":"2024","journal-title":"JCI Insight"},{"key":"2026071304100885000_2026.07.08.737074v1.9","doi-asserted-by":"crossref","unstructured":"Debrabander, Q. et al. 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