Immune Reconstitution and Antigenic Exposure History Shape Virus-Specific Humoral Immunity in People with HIV

SUMMARY CD4 + T-cell recovery is widely used to assess immune reconstitution in people with HIV, but its relationship to virus-specific humoral immunity across pathogens remains unclear. We characterized neutralizing activity against SARS-CoV-2, HIV-1, and influenza viruses in ART-treated, virologically suppressed individuals spanning distinct CD4 + T-cell levels. BA.5 was the dominant SARS-CoV-2 neutralization target across CD4 strata, whereas D614G neutralization increased with greater immune reconstitution. This gradient was largely absent for the antigenically divergent NB.1.8.1 and XFG variants. HIV-1 neutralization was inversely associated with CD4 + T-cell count, while influenza showed strain-dependent patterns. Neutralization-to-protection bridging preserved a CD4-associated gradient for D614G but not for highly immune-evasive variants. These findings show that immune reconstitution does not translate uniformly into antiviral humoral function. Instead, antibody profiles reflect host immune status, prior antigenic exposure, and viral antigenic evolution, supporting pathogen-specific functional assessment alongside conventional immune monitoring.