Elite and Viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell-tropism of circulating virus, evidence for HIV super-infection, cellular immune responses to HIV as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in-vitro viral suppression, even in the context of protective HLA alleles, predicts loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8-T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5 to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help to identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials.IMPORTANCE Few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as "HIV controllers". We have studied such HIV controllers who suddenly loose this ability and present with high in vivo viral replication and decays in their CD4+ T-cell counts, to identify potential immune and virological factors that were responsible for initial virus control. We identify in-vitro determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1 expressing CD8+ T-cells with a naïve immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals and may offer an important tool to anticipate viral rebound in individuals in clinical studies that include cART treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants.