Enhancing SIV-specific immunity in vivo by PD-1 blockade

Abstract

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 the blockade of co-inhibitory receptor programmed death-1 (PD-1) during chronic 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. Impressively, blockade was effective during the early (wk10) as well as late (∼wk90) 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 HIV/AIDS.

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

“…Splenocytes taken from mice treated in this way demonstrated increased IFNg release during in vitro culture with KLH, relative to those taken from mice treated with an isotype control antibody, which confirmed the potential of 10F.9G2 to enhance an on-going immune response. This result is consistent with other published studies looking at the effect of the PD-1/PD-L1 axis on response to foreign antigens (38,39), and supported the role of PD-L1 as a repressor of T-cell responses.…”

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…A component of PD-1 expression is regulated by increasing antigenemia; following the initiation of antivirals, PD-1 and PD-L1 expression decreases on HCV-and HIV-specific CD8 + T cells and MDCs, respectively (21,45,46). It is possible to block signaling through individual coinhibitory receptors, and the potential benefits of this strategy in controlling chronic viral infections have been discussed recently (7). By alleviating PD-L1-mediated inhibition in chronic infections, T cells are able to expand, thereby re-establishing high frequencies of existing polyfunctional virus-specific CD8 + T cells that can exert effective control over infection (35); this may not prove as beneficial when innate immune functions of DCs are impaired (40).…”

“…Because the PD-1/programmed death ligand 1 (PD-L1) axis operates primarily under conditions of sustained high levels of Ag stimulation and inadequate help (6) to turn off Ag-specific CD8 to prevent immune-mediated damage, chronic pathogens end up taking advantage of this inhibitory pathway to establish persistence in the host. This negative regulator has become a therapeutic target of choice because Ab blocking of PD-L1 reinvigorates exhausted CD8 cells to control chronic SIV infection in macaques (7). However, PD-1 expression patterns alone do not conclusively predict the clinical outcomes of HCV infection (8).…”

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

“…In mice, anti-PD-1 antibody can promote T-cell responses to a GVAX cellular vaccine (44) and to peptide-loaded DC vaccination (K. Bahjat et al; unpublished data). Although not a vaccine study, it is noteworthy that simian immunodeficiency virus (SIV)-infected monkeys treated with an anti-PD-1 antibody showed increased humoral responses to SIV antigens (45). Nivolumab was well tolerated when administered to cynomolgus monkeys as twice-weekly i.v.…”