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Although several viral and immune factors contribute to bNAb development, the genetic and environmental factors driving this response remain largely unknown. We performed combined cell-free DNA (cfDNA) and cell-free RNA (cfRNA) sequencing in 42 plasma samples from a longitudinal cohort of 14 PLWH (7 who develop bNAbs and 7 matched controls). This approach enabled us to non-invasively monitor the host transcriptome, viral genetic variation, and microbiome composition during HIV infection, and to identify molecular correlates of bNAb development. We find that development of bNAbs is associated with a transcriptomic signature of early immune activation characterized by elevated levels of MHC class I antigen presentation genes. This signature is independent of viral load or CD4 count and declines over time. In addition to host features, we recovered sufficient viral reads to reconstruct HIV consensus sequences, supporting the utility of cfRNA for viral genotyping. Finally, we also identified an enrichment of several microbial taxa in bNAb producers and increased levels of GB virus C (GBV-C), a non-pathogenic lymphotropic virus. Our findings suggest a distinct early immune activation profile in PLWH who develop bNAbs. More broadly, we show that combined cfDNA\/cfRNA sequencing can reveal relationships between a protective immunogenic response to HIV infection, the host immune system, and microbiome, highlighting its potential for biomarker discovery in future vaccine and therapeutic studies.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014066","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T17:22:08Z","timestamp":1775755328000},"page":"e1014066","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-free RNA reveals host and microbial correlates of broadly neutralizing antibody development against HIV"],"prefix":"10.1371","volume":"22","author":[{"given":"Mark","family":"Kowarsky","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Dalman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mira N.","family":"Moufarrej","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yike","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norma F.","family":"Neff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salim S.","family":"Abdool Karim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nigel","family":"Garrett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penny L.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6148-8132","authenticated-orcid":true,"given":"Joan","family":"Camunas-Soler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen R.","family":"Quake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ppat.1014066.ref001","volume-title":"Ending AIDS. 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