CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption

Harper, Justin; Gordon, Shari N.; Chan, Chi N.; Wang, Hong; Lindemuth, Emily; Galardi, Cristin M.; Falcinelli, Shane D.; Raines, Samuel L. M.; Read, Jenna; Nguyen, Kevin; McGary, Colleen S.; Nekorchuk, Michael; Busman‐Sahay, Kathleen; Schawalder, James; King, Colin T.; Pino, María; Micci, Luca; Cervasi, Barbara; Jean, Sherrie; Sanderson, Andrew; Johns, Brian A.; Koblansky, A. Alicia; Amrine-Madsen, Heather; Lifson, Jeffrey D.; Margolis, David M.; Silvestri, Guido; Bar, Katharine J.; Favre, David; Estes, Jacob D.; Paiardini, Mirko

doi:10.1038/s41591-020-0782-y

Cited by 79 publications

(83 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CTLA-4 blockade has been shown to increase CD4+ T-cell activation in previous studies. For example, CTLA-4 blockade, particularly when combined with PD-1 blockade, enhanced activation, proliferation, and expansion of LN and PB memory CD4+ and CD8+ T-cells in rhesus macaques infected with SIV [52]. Therefore, we interrogated the CD4+ T-cell subset further to examine the specialized subset of CD4+ T-cells known as Tfh cells [53,54].…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

et al. 2020

View full text Add to dashboard Cite

Studies have shown that blockade of CTLA-4 promoted the expansion of germinal center B-cells in viral infection or immunization with model antigens. Few studies have evaluated the immunological consequences of CTLA-4 blockade during immunization against relevant vaccine candidates. Here, we investigated the effects of CTLA-4 blockade on HIV virus-like particles (VLPs) vaccination in a C57BL/6J mouse model. We found that CTLA-4 blockade during HIV VLP immunization resulted in increased CD4+ T-cell activation, promoted the expansion of HIV envelope (Env)-specific follicular helper T cell (Tfh) cells, and significantly increased HIV Gag- and Env-specific IgG with higher avidity and antibody-dependent cellular cytotoxicity (ADCC) capabilities. Furthermore, after only a single immunization, CTLA-4 blockade accelerated T-cell dependent IgG class switching and the induction of significantly high serum levels of the B-cell survival factor, A proliferation-inducing ligand (APRIL). Although no significant increase in neutralizing antibodies was observed, increased levels of class-switched Env- and Gag-specific IgG are indicative of increased polyclonal B-cell activation, which demonstrated the ability to mediate and enhance ADCC in this study. Altogether, our findings show that CTLA-4 blockade can increase the levels of HIV antigen-specific B-cell and antigen-specific Tfh cell activity and impact humoral immune responses when combined with a clinically relevant HIV VLP-based vaccine.

show abstract

Section: Discussionmentioning

confidence: 99%

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Immunophenotyping 23-parameter flow cytometric analysis was perform on fresh PBMCs and mononuclear cells (10 6 cells) derived from LN biopsies, BAL, and lung. Immunophenotyping was performed using anti-human monoclonal antibodies (mAbs), which we (Harper et al, 2020;McGary et al, 2017;Micci et al, 2015;Pino et al, 2019) Fisher ( Supplementary Fig. 4).…”

Section: Single-cell Rna-seq Bioinformatic Analysismentioning

confidence: 99%

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Hoang

Pino

Boddapati

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

show abstract

“…Anti-PD1 (Human/rhesus chimeric antibody) alone or with vesatolimod had no statistical impact on the viral reserviors (216). Anti-PD1 (Human/rhesus chimeric antibody) and anti-CTLA4 dual blockade reduced the total and intact SIV DNA in CD4+ T cells as well as SIV DNA and RNA level in B cell follicles in lymph nodes (217).…”

Section: Pd1mentioning

confidence: 95%

“…Anti-PD1 (Human/rhesus chimeric antibody) and anti-CTLA4 dual blockade did not affect virus specific CD8 response and plasma viral load (217).…”

Section: Pd1mentioning

confidence: 99%

See 1 more Smart Citation

The Role of Immunomodulatory Receptors in the Pathogenesis of HIV Infection: A Therapeutic Opportunity for HIV Cure?

2020

View full text Add to dashboard Cite

Immune activation is the hallmark of HIV infection and plays a role in the pathogenesis of the disease. In the context of suppressed HIV RNA replication by combination antiretroviral therapy (cART), there remains immune activation which is associated to the HIV reservoirs. Persistent virus contributes to a sustained inflammatory environment promoting accumulation of "activated/exhausted" T cells with diminished effector function. These T cells show increased expression of immunomodulatory receptors including Programmed cell death protein (PD1), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA4), Lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain containing 3 (TIM3) among others. More importantly, recent reports had demonstrated that, HIV infected T cells express checkpoint receptors, contributing to their survival and promoting maintenance of the viral reservoir. Therapeutic strategies are focused on viral reservoir elimination and/or those to achieve sustained cART-free virologic remission. In this review, we will discuss the immunological basis and the latest advances of the use of checkpoint inhibitors to treat HIV infection.

show abstract

CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption

Cited by 79 publications

References 53 publications

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

The Role of Immunomodulatory Receptors in the Pathogenesis of HIV Infection: A Therapeutic Opportunity for HIV Cure?

Contact Info

Product

Resources

About