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Peer-reviewedCC BYNature Immunology

Innate immune imprints shape HIV-1 reservoir cell persistence during long-term antiretroviral therapy

  • Toong Seng Tan1,2
  • Weiwei Sun1,2
  • Ce Gao1,2
  • Mathias Viard3,4
  • Lucy C. Walters5,2
  • Mélanie Lancien2
  • Yuko Yuki3,4
  • Tram N. Van1,2
  • Carlos Casquero2
  • Xuan Guo2
  • Rebecca Hoh6
  • David W. Haas7
13 more authors
  • Nelson Michael8
  • Gregory Dale Kirk9
  • George A. Yendewa10
  • Rajesh Tim Gandhi11
  • Seble Kassaye12
  • Phyllis C. Tien13,14
  • Bruce D. Walker15,16,17,2
  • Michael J. Peluso6
  • Jeffrey M. Jacobson10
  • Steven G. Deeks6
  • Mary N Carrington3,4,2
  • Xu G. Yu1,2
  • Mathias D. Lichterfeld18,19
19 affiliations
  1. 1Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
  2. 2Ragon Institute of MGB, MIT and Harvard, Cambridge, MA, USA
  3. 3Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
  4. 4Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  5. 5Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
  6. 6Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, San Francisco, CA, USA
  7. 7Vanderbilt University Medical Center, Nashville, TN, USA
  8. 8U.S. Military HIV Research Program, Silver Spring, MD, USA
  9. 9Johns Hopkins University School of Public Health, Baltimore, MD, USA
  10. 10School of Medicine, Case Western Reserve University, Cleveland, OH, USA
  11. 11Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA
  12. 12Department of Medicine, Georgetown University Medical Center, Washington DC, USA
  13. 13Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
  14. 14Department of Veterans Affairs Medical Center, San Francisco, CA, USA
  15. 15Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
  16. 16Howard Hughes Medical Institute, Chevy Chase, MD, USA
  17. 17Institute for Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
  18. 18Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA. [email protected]
  19. 19Ragon Institute of MGB, MIT and Harvard, Cambridge, MA, USA. [email protected]
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Abstract

Host immune responses that can target and eliminate HIV-1 reservoir cells during suppressive antiretroviral therapy are poorly understood. Here, analyzing over 6,000 proviral DNA amplicons from 104 individuals on long-term antiretroviral therapy, we found that carriers of HLA-C2 allotypes, which promote NK cell education via interactions with KIR2DL1, exhibited lower frequencies of intact proviruses. No protective effects of HLA-C2 alleles were observed during untreated infection, suggesting a selective vulnerability of reservoir cells to NK-cell-mediated immune activity under antiretroviral therapy. Supporting this, frequencies of KIR2DL1 + NK cells, particularly those coexpressing the activating HLA-E receptor NKG2C, were inversely correlated with frequencies of intact proviruses. Moreover, viral protein U variants that strongly downregulate HLA-C, increasing a missing-self response by KIR2DL1 + NK cells, were associated with smaller reservoirs in carriers of HLA-C2. Infected cells surviving long-term displayed elevated HLA-C expression, consistent with in vivo selection for resistance to KIR2DL1 + NK-cell-mediated immune clearance. Immune activity of KIR2DL1 + NK cells against viral reservoir cells was enhanced by NKG2C–HLA-E interactions, as sequence variants in HLA-E-restricted HIV-1 epitopes reduced NKG2C-dependent NK cell activation and were associated with higher frequencies of intact proviruses. These findings underscore the critical influence of host and viral genetic variation on reservoir persistence and highlight opportunities for leveraging innate immunity in HIV cure strategies.

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Cite

BibTeXRIS
BibTeX
@article{tan2026innate,
  title = {{Innate immune imprints shape HIV-1 reservoir cell persistence during long-term antiretroviral therapy}},
  author = {Toong Seng Tan and Weiwei Sun and Ce Gao and Mathias Viard and Lucy C. Walters and Mélanie Lancien and Yuko Yuki and Tram N. Van and Carlos Casquero and Xuan Guo and Rebecca Hoh and David W. Haas and Nelson Michael and Gregory Dale Kirk and George A. Yendewa and Rajesh Tim Gandhi and Seble Kassaye and Phyllis C. Tien and Bruce D. Walker and Michael J. Peluso and Jeffrey M. Jacobson and Steven G. Deeks and Mary N Carrington and Xu G. Yu and Mathias D. Lichterfeld},
  journal = {Nature Immunology},
  year = {2026},
  month = sep,
  doi = {10.1038/s41590-026-02637-w},
  url = {https://doi.org/10.1038/s41590-026-02637-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Innate immune imprints shape HIV-1 reservoir cell persistence during long-term antiretroviral therapy
AU  - Toong Seng Tan
AU  - Weiwei Sun
AU  - Ce Gao
AU  - Mathias Viard
AU  - Lucy C. Walters
AU  - Mélanie Lancien
AU  - Yuko Yuki
AU  - Tram N. Van
AU  - Carlos Casquero
AU  - Xuan Guo
AU  - Rebecca Hoh
AU  - David W. Haas
AU  - Nelson Michael
AU  - Gregory Dale Kirk
AU  - George A. Yendewa
AU  - Rajesh Tim Gandhi
AU  - Seble Kassaye
AU  - Phyllis C. Tien
AU  - Bruce D. Walker
AU  - Michael J. Peluso
AU  - Jeffrey M. Jacobson
AU  - Steven G. Deeks
AU  - Mary N Carrington
AU  - Xu G. Yu
AU  - Mathias D. Lichterfeld
PY  - 2026
DA  - 2026/09/01
JO  - Nature Immunology
DO  - 10.1038/s41590-026-02637-w
UR  - https://doi.org/10.1038/s41590-026-02637-w
AB  - Host immune responses that can target and eliminate HIV-1 reservoir cells during suppressive antiretroviral therapy are poorly understood. Here, analyzing over 6,000 proviral DNA amplicons from 104 individuals on long-term antiretroviral therapy, we found that carriers of HLA-C2 allotypes, which promote NK cell education via interactions with KIR2DL1, exhibited lower frequencies of intact proviruses. No protective effects of HLA-C2 alleles were observed during untreated infection, suggesting a selective vulnerability of reservoir cells to NK-cell-mediated immune activity under antiretroviral therapy. Supporting this, frequencies of KIR2DL1 + NK cells, particularly those coexpressing the activating HLA-E receptor NKG2C, were inversely correlated with frequencies of intact proviruses. Moreover, viral protein U variants that strongly downregulate HLA-C, increasing a missing-self response by KIR2DL1 + NK cells, were associated with smaller reservoirs in carriers of HLA-C2. Infected cells surviving long-term displayed elevated HLA-C expression, consistent with in vivo selection for resistance to KIR2DL1 + NK-cell-mediated immune clearance. Immune activity of KIR2DL1 + NK cells against viral reservoir cells was enhanced by NKG2C–HLA-E interactions, as sequence variants in HLA-E-restricted HIV-1 epitopes reduced NKG2C-dependent NK cell activation and were associated with higher frequencies of intact proviruses. These findings underscore the critical influence of host and viral genetic variation on reservoir persistence and highlight opportunities for leveraging innate immunity in HIV cure strategies.
SN  - 1529-2908
SN  - 1529-2916
ER  -