Decreased CD4⁺ T cell counts drive aberrant B cell repertoire alterations in people living with HIV

Understanding the evolution of broadly neutralizing antibody (bNAb) activity in people living with HIV is crucial for vaccine design and immunization strategies. It has been proposed that antibody cross-reactive activity is associated with lower CD4⁺ T cell counts during people living with HIV, but the underlying mechanisms remain unclear. To further explore the correlation between antibody reactivity and CD4⁺ T cell counts, we recruited people living with HIV with varying CD4⁺ T cell counts: (i) CD4⁺ T cell ≤50 cells/μL, (ii) 50 cells/μL < CD4⁺ T cell ≤200 cells/μL, (iii) 200 cells/μL < CD4⁺ T cell ≤500 cells/μL, (iv) 500 cells/μL < CD4⁺ T cell. We assessed the antigen-specific antibodies in serum using SOSIP.664 trimers from four different subtypes. Immune repertoire sequencing was used to characterize the B cell receptor (BCR) repertoire of these individuals. The evaluation of antigen-specific antibodies with different SOSIP.664 trimers showed enhanced reactivity in individuals with low CD4⁺ T cell counts compared to those with high/normal CD4⁺ T cell counts. Analysis of antibody gene repertoires through BCR high throughput sequencing revealed an increased proportion of IgG with heavy chain complementarity-determining region 3 (CDRH3) loops exceeding 20 amino acids in individuals with CD4⁺ T cell counts below 50 cells/μL. Notably, the IGHV1-46 and IGHV4-34 germlines, which are suggestive of most polyreactive B cells, were preferentially used in individuals with low CD4⁺ T cell counts. These results suggest that limited engagement of CD4⁺ T cells could facilitate the survival of aberrant B cell repertoire with long CDRH3 regions.