Understanding PD-1 Blockade In Infectious Diseases

Introduction

The immune checkpoint receptor PD-1 (programmed cell death protein 1) preserves immunological homeostasis and avoids autoimmune disorders by regulating the apoptosis of T cells. The pdcd-1 gene in T and B cells encodes PD-1 (CD279) in humans. It reduces T cell and cytokine production through binding with ligands PD-L1 or PD-L2 (programmed death-ligand 1/2) to block the signaling of T cell receptors [1, 2]. As a result, several infectious diseases (caused by viruses, bacteria, fungi, and parasites), including HIV (Human Immunodeficiency Virus), COVID-19, and Dengue, are observed. However, the cycle of T-cell damage is crucial for blocking autoimmunity [3]. 

Figure 1: PD-1 pathway showing interaction between PD-1 and its ligands PD-L1/PD-L2

How to work PD-1 blockade in infectious diseases

Recent studies have demonstrated that blocking PD-1 stimulates functional T-cell production in the immune system. These cells proliferate cytokine induction activating virus-specific CD8+ cells, ultimately producing T cell exhaustion and viral control in HIV and HBV (Hepatitis B) [4]. Velu et al. reported high PD-1 expression on HIV-specific CD8+ T cells correlated with reduced proliferative capacity and increased apoptosis. Anti-PD-1 agents enhanced these cells' ability to grow and produce key cytokines like IFN-γ and TNF-α [5]. Moreover, PD-1 blockade also improves HBV-specific T cell responses in chronic HBV, leading to enhanced IL-2 production by HBV-specific T cells correlated with improved functionality and viral control post-PD-1 blockade [6, 7].

Figure 2: Increase in T-cell proliferation and cytokine production upon PD-1 blockade

Reduction of viral load

Frequent studies have reported that PD-1 blockade decreases viral load, which is investigated in chronic viral infections caused by HIV, HBV, and SIV (simian immunodeficiency virus). Other research has demonstrated that PD-1 inhibitors strengthen the immune response and regulate chronic infections by reducing viral tanks. 

Velu et al.’s experiment illustrated that the antibody PD-1 inhibitor (clone EH12.2H7) treats SIV-infected macaques after antiretroviral therapy (ART), leading to viral load reduction and CD8+ T cell improvement [8]. Another study indicated that viral load reduction is associated with increased T cell and IL-2 production after administrating anti-PD-1 agents in chronic HBV patients [6]. 

Figure 3: Reduction in viral load after PD-1 blockade in chronic infection models

Potential combination therapies

Many studies highlight the potential of combining PD-1 blockade with other therapeutic agents to achieve synergistic effects. This approach can amplify the immune response and target different aspects of viral pathogenesis. 

PD-1 inhibitors combine with latency-reversing chemicals, such as Bryostatin, leading to promising outcomes in the clearance of latent viruses during recent HIV research [9]. A study reported by Jubel et al. describes the combination therapy of vaccines (immunomodulatory medications) and anti-PD-1 agents to induce medicinal efficacy [10].  

Exploring new approaches 

The consistency of these findings across different viral models suggests broader applications for PD-1 blockade. Researchers can explore PD-1 inhibition in various chronic viral infections beyond HIV and HBV. For example, persistent infections like cytomegalovirus (CMV) or Epstein-Barr virus (EBV), which also exploit immune evasion mechanisms, could be potential targets for PD-1 blockade therapies [11].

In addition, the impact of PD-1 inhibition on the immune landscape in co-infections (HIV and tuberculosis) warrants investigation. By enhancing T cell responses, PD-1 blockade could help manage co-infections more effectively, addressing a significant challenge in global health [12].

Practical considerations

For researchers embarking on PD-1 blockade studies, optimizing experimental conditions, including antibody handling, dosing, and timing, is essential. Consistency in these parameters ensures reproducibility and comparability across studies. Immune responses must be monitored carefully to avoid potential adverse effects, such as hyper-activation leading to immunopathology [13]. 

Figure 4: Flow cytometry plots showing PD-1 expression on T cells before and after blockade 

Conclusion

Several studies frequently demonstrated that anti-PD-1 agents (PD-1 blockade) efficiently increase T cell activation, reduce viral load, and are used in combination therapies to prevent chronic infectious illnesses. Therefore, by understanding these well-established applications, scientists can investigate various novel usages and therapeutic tactics to manage the advanced level of contagious ailments. 

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References:

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2.  Bu MT, Yuan L, Klee AN, Freeman GJ. A Comparison of Murine PD-1 and PD-L1 Monoclonal Antibodies. Monoclon Antib Immunodiagn Immunother. 2022 Aug;41(4):202-209.

3.  https://www.bcm.edu/departments/molecular-virology-and-microbiology/emerging-infections-and-biodefense/introduction-to-infectious-diseases [Extracted information on May 22, 2024]

4.  Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating Exhausted T Cells by Blockade of the PD-1 Pathway. For Immunopathol Dis Therap. 2015;6(1-2):7-17.

5.   Velu V, Shetty RD, Larsson M, Shankar EM. Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. Retrovirology. 2015 Feb 8; 12:14. 

6.  Chua C, Salimzadeh L, Ma AT, Adeyi OA, Seo H, Boukhaled GM, Mehrotra A, et al. IL-2 produced by HBV-specific T cells as a biomarker of viral control and predictor of response to PD-1 therapy across clinical phases of chronic hepatitis B. Hepatol Commun. 2023 Dec 7;7(12): e0337. 

7.    Bertoletti A, Le Bert N. Immunotherapy for Chronic Hepatitis B Virus Infection. Gut Liver. 2018 Sep 15;12(5):497-507. 

8.   Velu V, Titanji K, Ahmed H, Shetty RD, Chennareddi LS, Freeman GJ, Ahmed R, Amara RR. PD-1 blockade following ART interruption enhances control of pathogenic SIV in rhesus macaques. Proc Natl Acad Sci U S A. 2022 Aug 16;119(33): e2202148119. 

9.    Fromentin R, DaFonseca S, Costiniuk CT, El-Far M, Procopio FA, Hecht FM, Hoh R, Deeks SG, Hazuda DJ, Lewin SR, Routy JP, Sékaly RP, Chomont N. PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals. Nat Commun. 2019 Feb 18;10(1):814. 

10.  Jubel JM, Barbati ZR, Burger C, Wirtz DC, Schildberg FA. The Role of PD-1 in Acute and Chronic Infection. Front Immunol. 2020 Mar 24; 11:487. 

11.  Baron M, Soulié C, Lavolé A, Assoumou L, Abbar B, Fouquet B, et al. The French Cooperative Thoracic Intergroup Ifct Chiva-Investigators, The Anrs Co OncoVIHAC Study Group. Impact of Anti PD-1 Immunotherapy on HIV Reservoir and Anti-Viral Immune Responses in People Living with HIV and Cancer. Cells. 2022 Mar 17;11(6):1015.

12.  Wykes MN, Lewin SR. Immune checkpoint blockade in infectious diseases. Nat Rev Immunol. 2018 Feb;18(2):91-104. 

13.  Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54.