α4 Integrin blockade impairs CD8+ T cell neuroimmune surveillance following SIV infection
Pabitra B. Pal, Sonny R. Elizaldi, Giovanne B. Diniz, Ravi Prakash Rai, Yashavanth Shaan Lakshmanappa, Anil Verma, Daniel Rossmiller, Jesse Kaufman, Rahul Srivastava, Sean Ott, Carissa T. Erices, Kayla Schwartz, Danielle Beckman, Zhong-Min Ma, Alex Petkov, Daniel Newhouse, Dhivyaa Rajasundaram, John H. Morrison, Reben Raeman, Smita S. Iyer
Pabitra B. Pal, Sonny R. Elizaldi, Giovanne B. Diniz, Ravi Prakash Rai, Yashavanth Shaan Lakshmanappa, Anil Verma, Daniel Rossmiller, Jesse Kaufman, Rahul Srivastava, Sean Ott, Carissa T. Erices, Kayla Schwartz, Danielle Beckman, Zhong-Min Ma, Alex Petkov, Daniel Newhouse, Dhivyaa Rajasundaram, John H. Morrison, Reben Raeman, Smita S. Iyer
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Research Article AIDS/HIV Immunology

α4 Integrin blockade impairs CD8+ T cell neuroimmune surveillance following SIV infection

Abstract

Integrin-targeted therapies are under investigation for HIV-associated neuroinflammation, yet their effect on CNS antiviral 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.

Authors

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

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Figure 6

α4 Blockade selectively reduces integrin-dependent T cell recruitment to the brain parenchyma.

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α4 Blockade selectively reduces integrin-dependent T cell recruitment to...
(A) Frequencies of total CD4+ T cells in brain parenchyma of α4- and IgG-treated macaques at week 3 after infection. (B) CD4+ T cell frequencies in spinal cord, skull marrow, and femur. Total PBMCs were stimulated with phorbol 12-myristate 13-acetate (PMA) plus ionomycin for 5 hours. Representative intracellular staining profiles shown for cytokine and cytolytic molecules in (C) CD4+ T cells and (D) CD8+ T cells (n = 3, IgG; n = 4, α4). (E) Flow plot of CCR5/CXCR3 expression in CD28– and CD28+ CD4+ T cells in brain. (F) Correlation between CD28–CXCR3+CD4+ T cell frequency and vRNA copies in hippocampal and PFC gray matter (Spearman). (G) Inverse correlation between α4β7+CD8+ T cell frequency and hippocampal vRNA (Spearman). (H and I) Frequencies of (I) α4β7+ and (H) α4β1+ CD4+ and CD8+ T cells in brain parenchyma and spleen Chr, chronic SIV. Data represent individual animals; lines indicate medians. *P < 0.05, unpaired t test. Experiments are representative of at least 3 independent replicates.