PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques

Shetty, Ravi Dyavar; Velu, Vijayakumar; Titanji, Kehmia; Bosinger, Steven E.; Freeman, Gordon J.; Silvestri, Guido; Amara, Rama Rao

doi:10.1172/jci60612

Cited by 138 publications

(100 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The noncanonical pyroptosis pathway can be activated by intracellular lipopolysaccharide (LPS) (38), the major structural element of the outer membrane in Gram-negative bacteria. The plasma LPS level was elevated in HIV-1 chronically infected individuals and SIV chronically infected rhesus macaques (45,46). Recently, it was also documented that 14 and 28 days after SIV infection, the gut epithelial barrier was compromised (47,48), and LPS levels in the colon and mesenteric lymph nodes were significantly increased in rhesus macaques (48).…”

Section: Discussionmentioning

confidence: 97%

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 ⁺ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Demers

et al. 2016

J Virol

View full text Add to dashboard Cite

Lymphoid tissues (LTs) are the principal sites where human immunodeficiency virus type 1 (HIV-1) replicates and virus-host interactions take place, resulting in immunopathology in the form of inflammation, immune activation, and CD4؉ T cell death. The HIV-1 pathogenesis in LTs has been extensively studied; however, our understanding of the virus-host interactions in the very early stages of infection remains incomplete. We investigated virus-host interactions in the rectal draining lymph nodes (dLNs) of rhesus macaques at different times after intrarectal inoculation (days postinoculation [dpi]) with simian immunodeficiency virus (SIV). At 3 dpi, 103 differentially expressed genes (DEGs) were detected using next-generation mRNA sequencing (RNA-seq). At 6 and 10 dpi, concomitant with increased SIV replication, 366 and 1,350 DEGs were detected, respectively, including upregulation of genes encoding proteins that play a role in innate antiviral immune responses, inflammation, and immune activation. Notably, genes (IFI16, caspase-1, and interleukin 1␤ [IL-1␤]) in the canonical pyroptosis pathway were significantly upregulated in expression. We further validated increased pyroptosis using flow cytometry and found that the number of CD4 Secondary lymphoid tissues (LTs) are the principal sites where human immunodeficiency virus type 1 (HIV-1) replicates and host-virus interactions take place, resulting in immune activation, inflammation, CD4 ϩ T cell death, and ultimately immune deficiency (1-3). However, the mechanisms underlying immunopathogenesis in LTs during very early infection, especially CD4 ϩ T cell death, remain incompletely understood. CD4 ϩ T cell death is a hallmark of disease progression in HIV-1 infection. To date, several mechanisms have been proposed to explain CD4 ϩ T cell death during HIV-1 infection in LTs. First, CD4ϩ T cell death results directly from HIV-1 productive infection via viral cytopathic effect. However, only a small fraction of total CD4 ϩ T cells in LTs are productively infected by HIV-1 (4, 5); therefore, pathogenic effect alone is not sufficient to account for the overall CD4 ϩ T cell death in vivo. Another proposed mechanism is apoptosis in HIV-1 uninfected bystander CD4 ϩ T cells mediated through Fas and TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) signaling (6-8). It was also demonstrated that HIV-1 Gp120 protein, expressed on the mem-

show abstract

Section: Discussionmentioning

confidence: 97%

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 ⁺ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Demers

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…Blockade of PD-1/PD-L1 interaction has been shown, both in vitro and in vivo, to reverse the exhaustion and restore the function of T cells (29)(30)(31)(32). Although HIV-1 has been reported to use many T-cell coinhibitory pathways, including PD-1/PD-L1, to evade control by the immune system, the viral factors by which HIV-1 induces upregulation of many T-cell coinhibitory molecules remain to be fully elucidated.…”

mentioning

confidence: 99%

HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

Planès

BenMohamed

Leghmari

et al. 2014

J Virol

View full text Add to dashboard Cite

Chronic human immunodeficiency virus type 1 (HIV-1) infection is associated with induction of T-cell coinhibitory pathways. However, the mechanisms by which HIV-1 induces upregulation of coinhibitory molecules remain to be fully elucidated. The aim of the present study was to determine whether and how HIV-1 Tat protein, an immunosuppressive viral factor, induces the PD-1/PD-L1 coinhibitory pathway on human dendritic cells (DCs). We found that treatment of DCs with whole HIV-1 Tat IMPORTANCEThe objective of this study was to investigate the effect of human immunodeficiency virus type 1 (HIV-1) Tat on the PD-1/PD-L1 coinhibitory pathway on human monocyte-derived dendritic cells (MoDCs). We found that treatment of MoDCs from either healthy or HIV-1-infected patients with HIV-1 Tat protein stimulated the expression of PD-L1. We demonstrate that this stimulation was mediated through an indirect mechanism, involving tumor necrosis factor alpha (TNF-␣) and Toll-like receptor 4 (TLR4) pathways, and resulted in compromised ability of Tat-treated MoDCs to functionally stimulate T-cell proliferation.

show abstract

“…On the contrary, other reports have shown that PD-1 is responsible of some characteristics of the hiperimmune activation (Holm et al, 2008;Nakanjako et al, 2011;. Blockade of the PD-1 pathway during SIV infection reduces the expression of activation markers in T cells and, importantly, reduces the translocation of bacterial products in the colorectal tissue of rhesus macaques (Shetty et al, 2012).…”

Section: Factors Contributing To Pd-1 and Pd-l1 Over-expression Durinmentioning

confidence: 94%

Co-Inhibitory Molecule Programmed Death-1 and Its Ligands: A New Alternative Therapy for Human Immunodeficiency Virus Infection?

Leon-Flores¹

2012

American Journal of Infectious Diseases

View full text Add to dashboard Cite

Chronic viral infections are characterized by the up-regulation of a set of immunomodulatory receptors. The over-expression of co-inhibitory molecules on T cells leads to a dysfunctional T cell response with an "exhausted" phenotype. Programmed Death-1 (PD-1) is a molecule that exerts an inhibitory signal on the T cell receptor when it binds to the PD-L1 or PD-L2 ligands present on antigen-presenting cells. Also, the expression of these molecules has been associated to the loss of T cell functions as well as clinical markers of the progression of HIV infection. The study of these molecules has gained attention due to reports indicating that blockade of PD-1 pathway could partially reconstitute T cell functions. In fact, this mechanism has been proposed as an alternative treatment for some chronic viral infections such as HIV infection. This review is focused on those mechanisms that might be favouring the over-expression of PD-1 and its ligands during HIV infection and on the possible new approaches that, by reducing its expression, might represent new strategies for the treatment of HIV infection. Knowing the exact mechanism leading to PD-1, PD-L1 and PDL2 expression in physiologic and pathological conditions is essential for the development of successful treatments. Novel molecular mechanisms inhibiting PD-1 activation might have potential therapeutic use not only in HIV infection but also in other diseases.

show abstract

PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques

Cited by 138 publications

References 22 publications

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 ⁺ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 ⁺ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

Co-Inhibitory Molecule Programmed Death-1 and Its Ligands: A New Alternative Therapy for Human Immunodeficiency Virus Infection?

Contact Info

Product

Resources

About

PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques

Cited by 138 publications

References 22 publications

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 + T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 + T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

Co-Inhibitory Molecule Programmed Death-1 and Its Ligands: A New Alternative Therapy for Human Immunodeficiency Virus Infection?

Contact Info

Product

Resources

About

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 ⁺ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 ⁺ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues