Enhancing SIV-Specific Immunity In Vivo by PD-1 Blockade

By V. Velu, K. Titanji, Baogong Zhu, S. Husain, Annette Pladevega, L. Lai, T. Vanderford, L. Chennareddi, G. Silvestri, G. Freeman and 2 more. Nature, 2008

779 citations recorded by the source corpus.

Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1) during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late (∼week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections.

Subfields: Immunology, Virology

View Paper: https://www.semanticscholar.org/paper/094131ce14d68942640f98b9e3f58f272e8ba543

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. E. Wherry
2. D. Pardoll
3. Lieping Chen
4. Rafi Ahmed
5. A. Schietinger
6. G. Freeman
7. P. Greenberg
8. K. Araki

In Virology

1. K. Araki
2. Rafi Ahmed

Citations in the corpus

• Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production (2013, background): “Recent studies in nonhuman primates have shown partial control of viral load after anti–PD-1 treatment (Finnefrock et al., 2009; Velu et al., 2009).”
• Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection (2010, background): “Involvement of the PD-1 pathway has also been shown in various chronic viral infections including HIV, hepatitis B virus, and HCV in humans (4, 5), and during simian immunodeficiency virus infection in nonhuman primates (6).”
• Redefining chronic viral infection. (2009, positive): “vivo blockade of this pathway enhances the SIV-specific antibody response in primates (Velu et al., 2008).”
• B cells in HIV infection and disease (2009, background): “In this regard, recent findings from a pathogenic SIV infection model indicate that in vivo treatment with antibodies that block the inhibitory receptor PD1 can improve B-cell response”
• Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction (2013, positive): “Blocking the PD-1 pathway has demonstrated therapeutic benefits in vivo in both LCMV-infected mice and SIV-infected macaques by increasing T cell function and viral clearance [72,95].”
• CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Several chronic infections, such as LCMV,HIV, HBV, and HCV, are associated with increased IL-10 production (147), and polymorphisms in the IL-10 promoter that result in lower IL-10 expression can lead to better control of chronic infections (148–150).”
• Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy (2014, background): “135 Yes 24 (35) 15 (62) 9 (38) 14 (58) 10 (42)”
• The blockade of immune checkpoints in cancer immunotherapy (2012, background): “Therefore, although PD1 blockade is typically viewed as enhancing the activity of effector T cells in tissues and in the tumour microenvironment, it also probably enhances NK cell activity in tumours and tissues and may also enhance antibody production either indirectly or through direct effects on ”
• PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses (2013, background): “Blockade of both CTLA-4 and PD-1 is also being actively investigated for reversing immune dysfunction and viral persistence in chronic hepatitis B and HIV infection (29, 30).”