Integrin-targeted therapies are under investigation for HIV-associated neuroinflammation, yet their effect on CNS antiviral immunity remains undefined. We examined the role of alpha 4 integrin in T cell-mediated neuroimmune surveillance using SIV-infected macaques with alpha 4 blockade and T cell-specific alpha 4-deficient mice. In macaques, alpha 4 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 alpha 4 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 alpha 4 beta 7* CD8* T cells correlated inversely, implicating impaired CD8* Tem recruitment in elevated parenchymal viral burden. In mice, alpha 4 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 alpha 4 integrin governs CD8-mediated neuroimmune surveillance through coordinated cellular positioning, with blockade enabling viral seeding while disrupting spatially organized antiviral defense.

We evaluate the efficacy and immunogenicity of HIV clade A/E A244 envelope (Env) immunogens with the 23 amino acids of variable region 1 deleted (ΔV1) or retained (wild-type [WT]) in macaques. Only the ΔV1 regimen significantly reduces the risk of mucosal acquisition of clade C simian/human immunodeficiency virus (SHIV)1157(QNE)Y173H versus controls, providing 81% efficacy and leaving 10 of 12 immunized animals uninfected. ΔV1 vaccination induces higher systemic antibody-dependent cellular cytotoxicity (ADCC) targeting helical-V2 and anti-inflammatory myeloid cells, which, together with IL-17+NKp44+ innate lymphoid cells (ILCs) and systemic PD-1+ helper T cells, correlated with reduced infection risk. By contrast, WT immunization induces higher IL-15, CCR2+pDC, and gp70/V1V2-biased responses, which, along with mucosal IFN-γ+NKG2A-NKp44- ILCs, were associated with increased susceptibility. Ex vivo, ΔV1 gp120 reduced CCR5 expression on CD4+ T cells relative to WT gp120, consistent with the anti-inflammatory mucosal response by ΔV1-vaccine regimens in vivo. Thus, V1 deletion promotes an anti-inflammatory mucosal landscape less permissive to HIV seeding and dissemination following virus exposure.

Abstract Chikungunya virus (CHIKV) causes periodic outbreaks and is endemic in more than 110 countries. VIMKUNYA, a CHIKV virus-like particle (CHIKV VLP) vaccine, was recently approved by regulators in the United States, European Union, and United Kingdom. Efficacy of VIMKUNYA in endemic settings is difficult to evaluate due to outbreak unpredictability. We used cynomolgus macaques, which model human CHIKV viremia and disease, to assess CHIKV VLP vaccine efficacy. Doses as low as 1.25 μg of CHIKV VLP with aluminum hydroxide adjuvant and passively transferred IgG from vaccinated humans significantly reduced viremia, disease, and joint pathology. Animals that received IgG doses resulting in mean reciprocal 80% neutralization titers of 35, well below the predicted protective threshold of ≥100, exhibited improved clinical outcomes compared with CHIKV-infected control animals, suggesting clinical benefits may occur at lower antibody levels. These findings demonstrate immunogenicity and protective efficacy of CHIKV VLP and relevance of neutralizing antibodies in protection, reinforcing its use in humans to protect against chikungunya disease.

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.

IntroductionLung diseases are widespread worldwide. Pulmonary immunity plays a vital role against lung pathogens, including SARS-CoV-2 infection. Understanding the pathogenesis, including the development of local immune responses to infection, is fundamental for developing interventions to control the viral infection.MethodsUsing immunohistochemistry, we investigated the distribution of immune cells in the lungs of rhesus macaques experimentally infected with SARS-CoV-2 and euthanized 11–14 days later.ResultsTertiary lymphoid tissue was found in all SARS-CoV-2 infected animals. The number (13.9 vs 1.5 iPLT number/ lung cm2), size (25992 vs 13946 µm2) and total area (0.46 vs 0.02 mm2 iPLT/ lung cm2) of the lymphoid tissue aggregations were significantly higher in SARS-CoV-2 infected animals than that of normal controls. This induced pulmonary lymphoid tissues comprised B cells, T cells, CD169 macrophages, and follicular dendritic cells with evidence of lymphocyte priming and differentiation.DiscussionThe results suggest local immunity plays an important role in the SARS-CoV-2 infection. Further study of pulmonary immunity could lead to new interventions to develop vaccine strategies and discover new immune-regulatory biomarkers in monitoring and controlling SARS-CoV-2 infection and other lung diseases.

Definitive data demonstrating the utility of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) for treating immunocompromised patients remains elusive. To better understand the mechanism of action of CCP, we studied viral replication and disease progression in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected hamsters treated with CCP obtained from recovered COVID-19 patients that were also vaccinated with an mRNA vaccine, hereafter referred to as Vaxplas. Vaxplas transiently enhanced disease severity and lung pathology in hamsters treated near peak viral replication due to immune complex and activated complement deposition in pulmonary endothelium, and recruitment of M1 proinflammatory macrophages into the lung parenchyma. However, aside from one report, transient enhanced disease has not been reported in CCP recipient patients, and the transient enhanced disease in Vaxplas hamsters may have been due to mismatched species IgG-FcR interactions, infusion timing, or other experimental factors. Despite transient disease enhancement, Vaxplas dramatically reduced virus replication in lungs and improved infection outcome in SARS-CoV-2-infected hamsters.

AbstractSystemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIVmac251 acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17+NKp44+ innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.6% was preserved with V2-TTB NPs. The deleterious effects of NPs were linked to preferential recruitment of mucosal plasmacytoid dendritic cells (pDCs), reduction of protective mucosal NKp44+ ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ+NKG2A-NKp44-ILCs, and increased levels of mucosal activated Ki67+CD4+ T cells, a potential target for virus infection. V2-TTB NP mucosal boosting rescued vaccine efficacy, likely via high avidity V2-specific antibodies mediating ADCC, and higher frequencies of mucosal NKp44+ ILCs and of ∆V1gp120 binding antibody-secreting B cells in the rectal mucosa. These findings emphasize the central role of systemic immunization and mucosal V2-specific antibodies in the protection afforded by ΔV1 envelope immunogens and encourage careful evaluation of vaccine delivery platforms to avoid inducing immune responses favorable to HIV transmission.

CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS) - known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Despite viral suppression with ART, acute infection led to significant depletion of CNS CD4 T cells, persisting into the chronic phase. These findings underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our results offer insights for potential T cell-focused interventions while also underscoring the challenges in eradicating HIV from the CNS, even with effective ART.

The utility of COVID-19 convalescent plasma (CCP) for treatment of immunocompromised patients who are not able to mount a protective antibody response against SARS-CoV-2 and who have contraindications or adverse effects from currently available antivirals remains unclear. To better understand the mechanism of protection in CCP, we studied viral replication and disease progression in SARS-CoV-2 infected hamsters treated with CCP plasma obtained from recovered COVID patients that had also been vaccinated with an mRNA vaccine, hereafter referred to as Vaxplas. We found that Vaxplas dramatically reduced virus replication in the lungs and improved infection outcome in SARS-CoV-2 infected hamsters. However, we also found that Vaxplas transiently enhanced disease severity and lung pathology in treated animals likely due to the deposition of immune complexes, activation of complement and recruitment of increased numbers of macrophages with an M1 proinflammatory phenotype into the lung parenchyma.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)—known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.

Pulmonary immunity against SARS-CoV-2 infection has not been well studied. This study investigated the distribution of immune cells int the lungs of 8 rhesus macaques experimentally infected with SARS-CoV-2, and euthanized 11-14 days later. Using immunohistochemistry, inducible bronchus-associated lymphoid tissue was found in all animals. The inducible bronchus-associated lymphoid tissues were composed of B cells, T cells, and follicular dendritic cells with evidence of lymphocyte priming and differentiation. This suggests local immunity plays an important role in the SARS-CoV-2 infection. Further study of local immunity in the lung would benefit our understanding of SARS-CoV-2 pathogenesis and could lead to new interventions to control the SARS-CoV-2 infection and disease.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for other respiratory viral diseases. To investigate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam-infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analyses of the respiratory tract and evaluated systemic cytokine and Ab responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam-infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum at day 1 postinfection whereas CXCL10 was induced in all animals. Both groups mounted neutralizing Ab responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal airway cells isolated at day 14 postinfection revealed significant upregulation of multiple IFN-stimulated genes in infants compared with adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared with infants. Our study in rhesus macaque monkey dam-infant pairs suggests age-dependent differential airway responses to SARS-CoV-2 infection and describes a model that can be used to investigate SARS-CoV-2 pathogenesis between infants and adults.

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.

The global spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for respiratory viral diseases. To elucidate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam-infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analysis of the respiratory tract and evaluated systemic cytokine and antibody responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam-infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum while CXCL10 was induced in all animals. Both groups mounted neutralizing antibody (nAb) responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal tissue isolated at day 14 post-infection revealed significant upregulation of multiple interferon-stimulated genes in infants compared to adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix (ECM) composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared to infants. Our observations suggest age-dependent differential airway responses to SARS-CoV-2 infection that could explain the distinction in pathogenesis between infants and adults.

As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel SARS-CoV-2 variant designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and it was shown to have enhanced infectivity in vitro and decreased antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both variants exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most marked body weight loss among the 3 variants. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three variants. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the oropharynx but not in the lungs. In multi-virus in-vivo competition experiments, we found that B.1. (614G), epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the nasal cavity, B.1. (614G), gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) and WA-1 variants in hamsters. These results demonstrate enhanced virulence and high relative oropharyngeal replication of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) variant.

To understand susceptibility of wild California sea lions and Northern elephant seals to influenza A virus (IAV), we developed an ex vivo respiratory explant model and used it to compare infection kinetics for multiple IAV subtypes. We first established the approach using explants from colonized rhesus macaques, a model for human IAV. Trachea, bronchi, and lungs from 11 California sea lions, 2 Northern elephant seals, and 10 rhesus macaques were inoculated within 24 h postmortem with 6 strains representing 4 IAV subtypes. Explants from the 3 species showed similar IAV infection kinetics, with peak viral titers 48 to 72 h post-inoculation that increased by 2 to 4 log10 PFU/explant relative to the inoculum. Immunohistochemistry localized IAV infection to apical epithelial cells. These results demonstrate that respiratory tissue explants from wild marine mammals support IAV infection. In the absence of the ability to perform experimental infections of marine mammals, this ex vivo culture of respiratory tissues mirrors the in vivo environment and serves as a tool to study IAV susceptibility, host range, and tissue tropism. IMPORTANCE Although influenza A virus can infect marine mammals, a dearth of marine mammal cell lines and ethical and logistical challenges prohibiting experimental infections of living marine mammals mean that little is known about IAV infection kinetics in these species. We circumvented these limitations by adapting a respiratory tract explant model first to establish the approach with rhesus macaques and then for use with explants from wild marine mammals euthanized for nonrespiratory medical conditions. We observed that multiple strains representing 4 IAV subtypes infected trachea, bronchi, and lungs of macaques and marine mammals with variable peak titers and kinetics. This ex vivo model can define infection dynamics for IAV in marine mammals. Further, use of explants from animals euthanized for other reasons reduces use of animals in research.

Summary: Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.