ABSTRACT

Sindbis virus (SINV) infection of the central nervous system (CNS) provides a model for understanding the role of the immune response in recovery from alphavirus infection of neurons. Virus clearance occurred in three phases: clearance of infectious virus (days 3 to 7), clearance of viral RNA (days 8 to 60), and maintenance of low levels of viral RNA (>day 60). The antiviral immune response was initiated in the cervical lymph nodes with rapid extrafollicular production of plasmablasts secreting IgM, followed by germinal center production of IgG-secreting and memory B cells. The earliest inflammatory cells to enter the brain were CD8⁺ T cells, followed by CD4⁺ T cells and CD19⁺ B cells. During the clearance of infectious virus, effector lymphocytes in the CNS were primarily CD8⁺ T cells and IgM antibody-secreting cells (ASCs). During the clearance of viral RNA, there were more CD4⁺ than CD8⁺ T cells, and B cells included IgG and IgA ASCs. At late times after infection, ASCs in the CNS were primarily CD19⁺ CD38⁺ CD138⁻ Blimp-1⁺ plasmablasts, with few fully differentiated CD38⁻ CD138⁺ Blimp-1⁺ plasma cells. CD19⁺ CD38⁺ surface Ig⁺ memory B cells were also present. The level of antibody to SINV increased in the brain over time, and the proportion of SINV-specific ASCs increased from 15% of total ASCs at day 14 to 90% at 4 to 6 months, suggesting specific retention in the CNS during viral RNA persistence. B cells in the CNS continued to differentiate, as evidenced by accumulation of IgA ASCs not present in peripheral lymphoid tissue and downregulation of major histocompatibility complex (MHC) class II expression on plasmablasts. However, there was no evidence of germinal center activity or IgG avidity maturation within the CNS.