Abstract

The causes of individual variability in the length of time between human immunodeficiency virus (HIV) infection and the development of AIDS are incompletely understood. Here, we present a novel hypothesis: that the relative magnitude of responses to HIV mediated by CD4+ T regulatory (Treg) cells vs. CD4+ T effector (Teff) cells is a critical determinant of variability in AIDS progression rates. We use a simple mathematical model to show that this hypothesis can plausibly explain three qualitatively different outcomes of HIV infection - fast or slow progression to AIDS, and long-term non-progression to AIDS - based on individual variation in underlying T-cell response. This hypothesis also provides a unifying explanation for various other empirical observations, suggesting in particular that both aging and certain dual infections increase the rate of AIDS progression because they increase the strength of the Treg cell response. We discuss potential therapeutic implications of our results.