Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive...

Area of Science:

• Immunology
• Virology
• Vaccinology

Background:

• Live attenuated simian immunodeficiency virus (SIV) provides strong protection against virulent SIV infection.
• The precise mechanisms underlying this vaccine-induced protection remain incompletely understood.
• Understanding these mechanisms is crucial for developing safe and effective human immunodeficiency virus (HIV) vaccines.

Purpose of the Study:

• To investigate the impact of live attenuated SIV on T cell memory compartments.
• To explore the role of viral replication in maintaining vaccine-induced T cell responses.
• To elucidate mechanisms relevant for designing future HIV vaccine strategies.

Main Methods:

• Utilized a novel doxycycline-dependent, replication-competent live-attenuated SIVmac239Δnef (SIV-rtTAΔnef) in rhesus macaques.
• Compared viral loads and T cell populations (CD4+, CD8+, TEM2, TCM) between SIV-rtTAΔnef and SIVΔnef infected macaques.
• Analyzed T cell phenotype, gut-homing markers (α4β7), and intracellular cytokine production (IL-2, IFN-γ, TNF-α, IL-17).

Main Results:

• SIV-rtTAΔnef exhibited an attenuated phenotype with lower peak plasma viral RNA compared to SIVΔnef.
• Chronic infection with attenuated SIV profoundly skewed circulating T cells towards a CD28-CCR7- T-effector memory 2 (TEM2) phenotype.
• This TEM2 polarization was dependent on doxycycline-induced viral replication and also observed in gut-homing T cell populations.

Conclusions:

• Attenuated SIV infection significantly alters the T memory cell compartment towards a mature effector phenotype.
• The maintenance of this T cell skewing appears to necessitate persistent viral replication.
• Findings suggest that sustained viral replication may be a key factor in SIV vaccine efficacy, informing HIV vaccine design.