HIV-1 induces targeted down-regulation of the Ig gene-diversifying enzyme AID in the germinal center of infected lymphoid follicles (45.1)

Abstract

Abstract Class switching from IgM to IgG and IgA is essential for antiviral immunity and requires activation-induced cytidine deaminase (AID), an APOBEC family member with DNA-editing activity. Germinal center (GC) B cells express AID upon activation by CD4+ T cells through CD40 ligand (CD40L) and IL-4. HIV-1 is thought to impair IgG and IgA responses to viral antigens, opportunistic pathogens and vaccines by causing progressive loss of CD4+ T cells and by rendering B cells poorly responsive to CD4+ T cell help. It remains unknown whether HIV-1 targets AID to hamper protective IgG and IgA responses. We found that infected GCs contained less AID, but normal APOBEC3G, an AID-related RNA-editing protein. AID down-regulation was not associated with local loss of CD4+ T cells and CD40L, but rather correlated with decreased activation of AID-inducing transcription factors, such as NF-κB and STAT6, and with increased expression of feedback inhibitors of NF-κB and STAT6, including IκBα, SOCS1 and SOCS3. AID down-regulation also correlated with accumulation of the viral protein Nef in the GC and with trafficking of Nef within membrane channels connecting infected myeloid cells to B cells. Together with our recent in vitro studies showing that Nef penetrates B cells and inhibits class, the present in vivo data suggest that HIV-1 evades protective IgG and IgA responses by targeting the class switch recombinase machinery.