Phenotypic signatures of immune selection in HIV-1 reservoir cells

Nature. 2023 Feb;614(7947):309-317. doi: 10.1038/s41586-022-05538-8. Epub 2023 Jan 4.

Abstract

Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Retroviral Agents / pharmacology
  • Anti-Retroviral Agents / therapeutic use
  • CD28 Antigens
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • CD4-Positive T-Lymphocytes* / virology
  • Cell Survival
  • HIV Infections* / immunology
  • HIV Infections* / virology
  • HIV-1* / drug effects
  • HIV-1* / genetics
  • HIV-1* / immunology
  • HIV-1* / isolation & purification
  • Humans
  • Immunologic Memory
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Phenotype*
  • Proviruses / drug effects
  • Proviruses / genetics
  • Proviruses / isolation & purification
  • Receptors, Interleukin-21
  • Viral Load
  • Virus Latency* / drug effects

Substances

  • Anti-Retroviral Agents
  • CD44 protein, human
  • CD28 Antigens
  • IL7R protein, human
  • Receptors, Interleukin-21