Modeling HIV dynamics under broadly neutralizing antibodies: The potential role of cell-to-cell virus transmission

Cell-to-cell transmission of human immunodeficiency virus (HIV) presents a significant challenge to combination antiretroviral therapy (cART), as this mode of infection is markedly more efficient and often exhibits increased resistance to antiviral agents compared to cell-free viral infection. However, the impact of cell-to-cell virus transmission on the efficacy of broadly neutralizing antibody (bNAb) therapy remains unclear. In this study, we develop a mathematical model that incorporates both cell-free and cell-to-cell virus transmission, as well as antibody-sensitive and -resistant virus strains, to investigate HIV dynamics during bNAbs administration. The model is calibrated using clinical data from six responding infected individuals receiving VRC01 infusion. Numerical simulations using the best-fit parameter values suggest that, within the framework of our model, cell-to-cell virus transmission, particularly mediated by resistant infected cells, becomes the major route of CD4+ T cell infection during antibody treatment. Moreover, variations in the neutralization sensitivity of cell-to-cell virus transmission significantly influence intermediate-phase viral load. Furthermore, for both two- and three-dose regimens, while an experimental 28-day dosing interval delays viral rebound relative to a single dose, an optimized 44-day interval maximizes suppression. Crucially, exceeding this 44-day window by even one day resets the rebound time to the single-dose baseline. These results highlight the potential role of cell-to-cell transmission in sustaining HIV infection despite bNAb pressure and the need to optimize dosing regimens to improve outcomes. These model-based predictions warrant further experimental and clinical investigation.