Here, we aimed to decipher the role of CD4+ T-cell depletion in driving the HIV/SIV-associated gut dysfunction and progression to AIDS, by disrupting immune CD4+ T-cell homeostasis for over a year through repeated infusions of an anti-CD4 mAb to SIVsab-infected AGMs, a model of nonpathogenic SIV infection. Here, CD4 is linked to AIDS.