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ResearchIn-Press PreviewAIDS/HIVImmunology Open Access | 10.1172/JCI198730

α4 integrin blockade impairs CD8 T cell neuroimmune surveillance following SIV infection

Pabitra B. Pal,1 Sonny R. Elizaldi,2 Giovanne B. Diniz,2 Ravi Prakash Rai,3 Yashavanth Shaan Lakshmanappa,2 Anil Verma,2 Daniel Rossmiller,1 Jesse Kaufman,1 Rahul Srivastava,1 Sean Ott,2 Carissa T. Erices,2 Kayla Schwartz,2 Danielle Beckman,2 Zhong-Min Ma,2 Alex Petkov,1 Daniel Newhouse,4 Dhivyaa Rajasundaram,5 John H. Morrison,2 Reben Raeman,3 and Smita S. Iyer1

1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

2California National Primate Research Center, UC Davis, Davis, United States of America

3Organ Pathobiology and Therapeutics Institute, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Bruker Spatial Biology, Seattle, United States of America

5Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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Published February 24, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI198730.
Copyright © 2026, Pal et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 24, 2026 - Version history
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Abstract

Integrin-targeted therapies are under investigation for HIV associated neuroinflammation, yet their impact on CNS anti-viral immunity remains undefined. We examined the role of α4 integrin in T cell mediated neuroimmune surveillance using SIV-infected macaques with α4 blockade and T cell-specific α4-deficient mice. In macaques, α4 blockade preserved CD4 Th1 cell access to the brain parenchyma but impaired CD8 effector recruitment, disrupting antiviral control. Despite stable cerebrospinal fluid viral loads, hippocampal SIV RNA increased under blockade. Single-cell analyses revealed α4 enrichment in CD8 effector memory (TEM) cells; blockade reduced inferred CD8 TEM-monocyte interactions and heightened innate immune activation in the hippocampus. Microscopy demonstrated persistent SIV-induced microglial simplification despite treatment. Th1 CD4 effectors correlated positively with gray matter viral RNA, whereas α4β7⁺ CD8 T cells correlated inversely, implicating impaired CD8 TEM recruitment in elevated parenchymal viral burden. In mice, α4 proved dispensable for CD4 trafficking to inflamed brain but essential for CD8 effector access across CNS compartments and for both subsets to reach skull marrow. These findings establish that α4 integrin governs CD8-mediated neuroimmune surveillance through coordinated cellular positioning, with blockade enabling viral seeding while disrupting spatially organized antiviral defense.

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