Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques

Area of Science:

• Immunology
• Virology
• Pathogenesis

Background:

• Rapid progression to Acquired Immunodeficiency Syndrome (AIDS) is a major global health challenge.
• Simian Immunodeficiency Virus (SIV)-infected macaques serve as a crucial model for studying human immunodeficiency virus (HIV) pathogenesis.
• Understanding early events predicting rapid disease progression is vital for developing effective interventions.

Purpose of the Study:

• To investigate the role of activated memory B cells (mBAct) in the rapid progression of SIV infection.
• To identify early biomarkers associated with accelerated disease progression in SIV-macaque models.
• To explore the potential of targeting the programmed death-1 (PD-1) pathway to restore immune function.

Main Methods:

• Analysis of SIV-infected rhesus macaque immune cell populations, focusing on activated memory B cells (CD21-CD27+).
• Assessment of SIV-specific and non-specific antibody responses.
• In vitro and in vivo blockade of the programmed death-1 (PD-1) pathway.

Main Results:

• Pathogenic SIV infection rapidly depleted mBAct cells, with depletion severity correlating with disease progression speed.
• Rapid progressors showed sustained mBAct cell loss, impaired SIV-specific antibody production, and increased susceptibility to infections.
• mBAct cell depletion was linked to PD-1 expression, and PD-1 blockade improved cell survival and enhanced antibody responses.

Conclusions:

• Early depletion of mBAct cells is a strong predictor of rapid disease progression in pathogenic SIV infection.
• The PD-1 pathway plays a significant role in mBAct cell depletion and impaired humoral immunity during SIV infection.
• Targeting PD-1 may represent a therapeutic strategy to enhance immune responses in SIV-infected macaques.