Katie Fisher, Mauro Garcia, Giacomo S. Frattari, Chloé M. Naasz, Junlin Zhuo, Míriam Rosás-Umbert, Lisa L. Dietz, Anna Karina Juhl, Emma Falling Iversen, Rikke Olesen, Mariane H. Schleimann, Marie H. Pahus, Isik S. Johansen, Merle Henderson, Leah Carrere, Isabelle Roseto, Ce Gao, Xiaojuan Yu, Emily J. Fray, Beril Aydin, Donald Lubbeck, J. Lai, Francesco R. Simonetti, Ali Danesh, Itzayana Miller, Pilar Mendoza, Julia Niessl, Christian Gaebler, Michael S. Seaman, Daniel E. Kaufmann, Clara Lehmann, Henning Gruell, Florian Klein, Marina F. Caskey, Michel C. Nussenzweig, Martin Tolstrup, R. Brad Jones, Jesper Damsgaard Gunst, Janet D. Siliciano, Mathias Lichterfeld, Robert F. Siliciano, Ole S. Søgaard
Abstract Antiretroviral therapy (ART) interruption typically leads to rapid HIV-1 viral rebound in people with HIV-1. To develop an HIV-1 cure, insight into immunological mechanisms capable of preventing HIV-1 viral rebound is urgently needed. Here, we describe three exceptional post-intervention controllers (PICs) who maintained ART-free virological control for >6.5 years (ongoing), >7.5 years (ongoing) and 2.5 years following administration of broadly neutralizing antibodies. PICs had quantifiable genetically intact/inducible infectious proviral reservoirs that were increasingly clonal and located in nongenic/centromeric chromosomal regions, indicating immune-mediated selection. Potent autologous neutralizing antibodies and polyfunctional HIV-1-specific CD4 + and CD8 + T cell responses, pre-programmed for antigen response, were present before, and persisted during, ART interruption. In one PIC, viral rebound following 2.5 years of ART-free control was associated with accumulated viral mutations that resulted in escape from neutralizing antibody and T cell responses. Collectively, our findings support developing HIV-1 curative strategies aimed at enhancing pre-existing adaptive immune responses.