Successful approaches for eradication or cure of HIV-1 infection are likely to include immunological mechanisms, but remarkably little is known about how human immune responses can recognize and interact with the few HIV-1-infected cells that harbour genome-intact viral DNA, persist long term despite antiretroviral therapy and represent the main barrier to a cure. For a long time regarded as being completely shielded from host immune responses due to viral latency, these cells do, on closer examination with single-cell analytic techniques, display discrete footprints of immune selection, implying that human immune responses may be able to effectively engage and target at least some of these cells. The failure to eliminate rebound-competent virally infected cells in the majority of persons likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged from immune recognition or rely on sophisticated approaches for resisting immune-mediated killing. Understanding the fine-tuned interplay between host immune responses and viral reservoir cells will help to design improved interventions that exploit the immunological vulnerabilities of HIV-1 reservoir cells.