Decoding HIV Dynamics: The Role of Modeling in Understanding Viral Load Decay under Retroviral Therapy

Abstract

Mathematical modeling of HIV has changed the paradigm of slow replication and showed that in the order of magnitude of 10^9 infections occur per day. Here, the contributions of HIV modeling to the understanding of the viral dynamics under antiretroviral therapy (ART) are reviewed. Upon initiation of ART, a rapid first decay phase is observed, during which the viral load falls by as much as 99% within days. During this decay phase, the observed decay rate reflects the death rate of productively infected CD4+ cells. After a few weeks of treatment, the early decay phase is followed by the second decay phase, during which virus is produced by a secondary population of long-lived cells. Macrophages have long been suspected to be the source of the second-phase viremia, but more recent modeling studies found that their kinetics do not fit clinical data. The most likely candidate for the long-lived cell population are resting CD4+ T cells with slow integration. Based on the first- and second-phase decay rates, viral eradication should be achieved after several years of ART treatment. However, low-level viremia persists due the existence of a reservoir of latently infected CD4+ T cells. Modeling efforts have shown that this reservoir decays very slowly and is intrinsically stable. The latent reservoir is not maintained by ongoing viral replication, but instead is replenished by intermittent antigenic stimulation. These insights highlight the critical role mathematical modeling has played in advancing our understanding of HIV and the viral load dynamics under therapy.