Lymph node CXCR5+ NK cells associate with control of chronic SHIV infection

JCI Insight. 2022 Apr 22;7(8):e155601. doi: 10.1172/jci.insight.155601.


The persistence of virally infected cells as reservoirs despite effective antiretroviral therapy is a major barrier to an HIV/SIV cure. These reservoirs are predominately contained within cells present in the B cell follicles (BCFs) of secondary lymphoid tissues, a site that is characteristically difficult for most cytolytic antiviral effector cells to penetrate. Here, we identified a population of NK cells in macaque lymph nodes that expressed BCF-homing receptor CXCR5 and accumulated within BCFs during chronic SHIV infection. These CXCR5+ follicular NK cells exhibited an activated phenotype coupled with heightened effector functions and a unique transcriptome characterized by elevated expression of cytolytic mediators (e.g., perforin and granzymes, LAMP-1). CXCR5+ NK cells exhibited high expression of FcγRIIa and FcγRIIIa, suggesting a potential for elevated antibody-dependent effector functionality. Consistently, accumulation of CXCR5+ NK cells showed a strong inverse association with plasma viral load and the frequency of germinal center follicular Th cells that comprise a significant fraction of the viral reservoir. Moreover, CXCR5+ NK cells showed increased expression of transcripts associated with IL-12 and IL-15 signaling compared with the CXCR5- subset. Indeed, in vitro treatment with IL-12 and IL-15 enhanced the proliferation of CXCR5+ granzyme B+ NK cells. Our findings suggest that follicular homing NK cells might be important in immune control of chronic SHIV infection, and this may have important implications for HIV cure strategies.

Keywords: AIDS/HIV; Immunology; Innate immunity; NK cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • HIV Infections*
  • Humans
  • Interleukin-12 / metabolism
  • Interleukin-15* / metabolism
  • Killer Cells, Natural
  • Lymph Nodes
  • Receptors, CXCR5 / metabolism


  • CXCR5 protein, human
  • Interleukin-15
  • Receptors, CXCR5
  • Interleukin-12