2. Academic Validation
  3. Three immunoregulatory signatures define non-productive HIV infection in CD4+ T memory stem cells

Three immunoregulatory signatures define non-productive HIV infection in CD4+ T memory stem cells

  • bioRxiv. 2026 Mar 21:2026.03.20.713012. doi: 10.64898/2026.03.20.713012.
Giacomo M Butta 1 2,  Bremy Alburquerque 3,  Charlotte Kearns 1 2,  Yoav Hadas 4 3 5 6,  Max W VanDyck 1,  Susanna Scaglioni 1 2 7 8,  Noah Peña 1 2,  Hoi Tong Wong 1 2,  Elizabeth Levendosky 1 2,  Charles Gleason 1 2,  Xiao Lin 4 3 5 6,  Lara Manganaro 1 7 8,  Dalila Pinto 4 3 9 5 6,  Lubbertus C F Mulder 1 2 10,  Viviana Simon 1 2 10 11 12
Affiliations

Affiliations

  • 1 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7 Università degli Studi di Milano, Department of Pharmacological and Biomolecular Sciences, Milan, Italy.
  • 8 INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
  • 9 Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 10 The Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12 Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
PMID: 41889968 DOI: 10.64898/2026.03.20.713012
Abstract

The persistent HIV reservoir constitutes the main obstacle to curing HIV/AIDS disease. Our understanding of how non-productive HIV infections are established in primary human CD4+ T cells during the first round of Infection remains, however, incomplete. In this study, we leveraged the HIV reporter virus pMorpheus-V5 to delineate cellular expression patterns that are upregulated in non-productively infected primary CD4+ T memory stem cells (TSCM). We found that CD4+ TSCM harboring non-productive proviruses displayed a distinct transcriptomic signature comprising 118 upregulated genes. This non-productive expression profile was distinct from that of productively infected cells as well as from negative-exposed and mock-infected cells. Among the cellular genes most upregulated in CD4+ T cells harboring non-productive proviruses were CCR4-binding migratory chemokines (CCL22, CCL17), tryptophan catabolic Enzymes (IDO1, KYNU), and genes encoding cytoskeletal rearrangement proteins (BASP1, TNFAIP2). Intracellular flow cytometry-based analyses confirmed that non-productively infected CD4+ TSCM cells were enriched for CCL22 and IDO1 co-expression compared to the Other CD4+ memory subsets, underscoring a clear CD4+ T cell subset specificity for the upregulation of these two immune gene sets associated with non-productive infections. These findings suggest that primary human CD4+ TSCM harboring non-productive proviruses display a distinct immunoregulatory phenotype which may facilitate immune evasion and contribute to the persistence of the HIV reservoir.

Keywords

CCL22; CD4+ TSCM; HIV latency; HIV reservoir; HIV/AIDS; IDO1; Tregs; chemokines; immunoregulation; non-productive infection; tryptophan.

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