AAV long-term lymphocyte depletion in chronic LCMV separates B cell presence from antibody secretion

An immunology professor at the University of Basel, Switzerland (transcribed erroneously as Pinkwell; should be Daniel Pinschewer) introduces two lines of research: ① using AA.

• Long-lasting depletion tool: the heavy- and light-chain coding of depleting antibodies (anti-CD4/anti-CD8/anti-CD20, etc.) is encoded into the AAV genome; after intramuscular injection, muscle cells (episomal) continuously produce the antibody, so a single administration achieves durable lymphocyte depletion for >100 days; by contrast, conventionally passively injected antibodies are metabolized within about 1 month, and cells rebound.
• Tool advantages and comparisons: enables 'somatic knockout' in adult animals without genetic backcrossing, applicable to multiple strains such as FVB/NZB; two AAV strains can be combined to simultaneously deplete two subsets (e.g., B cells + CD8).
• Structural fidelity: traditional B-cell-deficient mice (JH-/-) lack marginal zone macrophages; AAV anti-CD20, while clearing B cells, preserves the marginal zone (because B cells were present early in ontogeny), thereby allowing more specific distinction of the functions of B cells themselves.
• Chronic LCMV model conclusions: after CD8 depletion, virus initially declines but rebounds after about 60-80 days (CD8 is responsible for final clearance); B-cell depletion leads to complete loss of viral control (consistent with B-cell knockout mice); dual depletion is no worse than B-cell depletion alone - without B cells, CD8 is ineffective.
• Mechanistic dissection: using 'B cells present but unable to secrete antibodies' (sIgM/AID double knockout) and 'receptor-specific but targeting an unrelated virus' (monoclonal BCR mice), it was shown that the physical presence of B cells (independent of antibody secretion capability or receptor specificity) is a prerequisite for maintaining normal antiviral CD4/CD8 (including Tfh) responses; however, clearance of chronic viral infection requires a 'specific antibody response'.
• Tolerance and HBV implications: neonatal (within 24h after birth) LCMV infection establishes lifelong carriage (analogous to the roughly 300 million HBV carriers worldwide); wild-type mice have liver/spleen viral loads 0.5-1 log lower than BCR-restricted mice; in carriers there are still small numbers of virus-specific CD4 T cells, about 1/4-1/3 of which have a Tfh phenotype, with a more oligoclonal TCR repertoire; exogenous CD4 supplementation boosts germinal centers and affinity-matured antibodies in neonatally infected mice by about 6-fold, suggesting antiviral Tfh responses could serve as a target for HBV 'functional cure'.