The article discusses the challenges and potential strategies for eliminating HIV-1 reservoir cells, which are the main barrier to a cure for HIV infection. Despite extensive research, no curative therapy is available for HIV-1, and the infection remains a chronic condition managed with antiretroviral therapy (ART). The article highlights that while HIV-1-infected cells are typically considered shielded from immune responses due to viral latency, recent studies using single-cell analytic techniques have revealed discrete footprints of immune selection, suggesting that human immune responses can engage and target these cells. However, the failure to eliminate these cells in most individuals likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged or resistant to immune-mediated killing. The article reviews the dynamics of HIV-1 reservoir cells, including the longitudinal evolution of intact versus defective proviruses, and the accumulation of intact proviruses in heterochromatin regions. It also discusses the role of immune responses, such as natural killer cells, type I interferon responses, and HIV-1-specific T cells, in targeting and eliminating these reservoir cells. The article further explores the resistance and immune evasion mechanisms of reservoir cells, including transcriptional profiling and phenotypic analysis, which suggest that these cells are optimized to resist host immune activity. Finally, the article outlines potential therapeutic approaches for targeting HIV-1 reservoir cells, including latency-reversing agents, immune checkpoint inhibitors, modifications of cell-intrinsic immune activity, and modulating adaptive immunity through therapeutic vaccines, broadly neutralizing antibodies, and chimeric antigen receptor T cells. The authors propose a sequential combinatorial approach that combines multiple immune system components to reduce the frequency of rebound-competent viral reservoir cells and induce a long-lasting, highly functional adaptive memory cell response to control viral rebound.The article discusses the challenges and potential strategies for eliminating HIV-1 reservoir cells, which are the main barrier to a cure for HIV infection. Despite extensive research, no curative therapy is available for HIV-1, and the infection remains a chronic condition managed with antiretroviral therapy (ART). The article highlights that while HIV-1-infected cells are typically considered shielded from immune responses due to viral latency, recent studies using single-cell analytic techniques have revealed discrete footprints of immune selection, suggesting that human immune responses can engage and target these cells. However, the failure to eliminate these cells in most individuals likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged or resistant to immune-mediated killing. The article reviews the dynamics of HIV-1 reservoir cells, including the longitudinal evolution of intact versus defective proviruses, and the accumulation of intact proviruses in heterochromatin regions. It also discusses the role of immune responses, such as natural killer cells, type I interferon responses, and HIV-1-specific T cells, in targeting and eliminating these reservoir cells. The article further explores the resistance and immune evasion mechanisms of reservoir cells, including transcriptional profiling and phenotypic analysis, which suggest that these cells are optimized to resist host immune activity. Finally, the article outlines potential therapeutic approaches for targeting HIV-1 reservoir cells, including latency-reversing agents, immune checkpoint inhibitors, modifications of cell-intrinsic immune activity, and modulating adaptive immunity through therapeutic vaccines, broadly neutralizing antibodies, and chimeric antigen receptor T cells. The authors propose a sequential combinatorial approach that combines multiple immune system components to reduce the frequency of rebound-competent viral reservoir cells and induce a long-lasting, highly functional adaptive memory cell response to control viral rebound.