Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells.. Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells.

The latent reservoir of HIV persists for decades in people living with HIV (PWH) on antiretroviral therapy (ART). To determine if persistence arises from the natural dynamics of memory CD4+ T cells harboring HIV, we compared the clonal dynamics of HIV proviruses to that of memory CD4+ T cell receptors (TCRβ) from the same PWH and from HIV-seronegative people. We show that clonal dominance of HIV proviruses and antigen-specific CD4+ T cells are similar but that the field’s understanding of the persistence of the less clonally dominant reservoir is significantly limited by undersampling. We demonstrate that increasing reservoir clonality over time and differential decay of intact and defective proviruses cannot be explained by mCD4+ T cell kinetics alone. Finally, we develop a stochastic model of TCRβ and proviruses that recapitulates experimental observations and suggests that HIV-specific negative selection mediates approximately 6% of intact and 2% of defective proviral clearance. Thus, HIV persistence is mostly, but not entirely, driven by natural mCD4+ T cell kinetics. Overall design: To test whether the natural physiology of memory CD4+ T cells (e.g., HIV as inert “passenger” hypothesis) is sufficient to explain reservoir clonality and dynamics or whether selective factors related to HIV infection itself are required to explain these observations, we generated longitudinal clonality data from memory CD4+ T cells in HIV seronegative individuals and from HIV proviruses and CD4s simultaneously from PWH on ART. We compared the longitudinal (~10 year) clonality of HIV proviruses (intact and defective) from resting CD4+ T cells with the longitudinal clonality of their putative carrier cells, resting memory CD4+ (rmCD4) T cells from the same blood samples from PWH on ART. We also compared proviral clonality of the replication competent reservoir at single time points from PWH on long-term ART with the clonality of rmCD4s from the same blood samples. To determine whether suppressed HIV infection itself is associated with significantly different mCD4 clonality, we compared the longitudinal cohort of PWH on ART to HIV-seronegative people matched on age, race, and sex. We identified antigen specific (CMV and HIV) mCD4 cells in a subset of people and compared their clonality and decay rates with that of HIV-infected cells and all mCD4s. To make these comparisons, we modeled clonotype abundance distributions and calculated clonality and diversity metrics. ***Adaptive Biotechnologies does not release raw data.***