This review focuses on the cell biology of HIV-1 latency and rebound, highlighting the challenges in developing a cure for HIV-1 infection. The primary barrier to a cure is the presence of transcriptionally latent proviruses in a small subset of memory CD4+ T cells, which can lead to viral rebound when antiretroviral therapy (ART) is interrupted. Despite the success of ART in blocking viral replication, it does not eliminate the viral reservoir, leading to chronic immune activation and the potential for viral rebound. The review discusses the molecular mechanisms that regulate HIV-1 transcription, including the role of host factors such as transcription initiation factors (NFAT, NF-κB), chromatin remodeling complexes (BAF, PBAF), and epigenetic silencing mechanisms. It emphasizes the importance of understanding the transitions between active effector cells and quiescent memory cells, which are not fully recapitulated in transformed cell models like Jurkat T-cells. Recent studies using primary cell models and ex vivo cellular systems have identified key factors that block HIV-1 transcription in memory CD4+ T cells, such as restrictive epigenetic features at the proviral promoter, cytoplasmic sequestration of transcription initiation factors, and low expression of the cellular transcription elongation factor P-TEFb. The "Shock and Kill" strategy, which aims to reactivate latent HIV-1 proviruses to clear persistently infected cells, is discussed, along with the need for effective latency-reversing agents (LRAs). The review also explores the dynamics of the HIV reservoir, including the clonal expansion of latently infected cells driven by homeostatic proliferation and antigen-mediated activation. It highlights the role of T-cell signaling mechanisms in stimulating P-TEFb biogenesis and reversing proviral epigenetic restrictions. Finally, the review delves into the chromatin organization of proviral HIV-1 and its epigenetic silencing, including the involvement of histone modifications, DNA methylation, and phase-separated nuclear condensates. It discusses the potential of epigenetic modifications to permanently silence HIV-1, as suggested by the "Block and Lock" strategy, and the challenges in achieving this goal. Keywords: HIV-1 latency, HIV-1 reservoir, Latency reversal, Epigenetic silencing, Transcription elongation, T-cell receptor signaling, P-TEFb, HIV-1 Tat, 7SK snRNPThis review focuses on the cell biology of HIV-1 latency and rebound, highlighting the challenges in developing a cure for HIV-1 infection. The primary barrier to a cure is the presence of transcriptionally latent proviruses in a small subset of memory CD4+ T cells, which can lead to viral rebound when antiretroviral therapy (ART) is interrupted. Despite the success of ART in blocking viral replication, it does not eliminate the viral reservoir, leading to chronic immune activation and the potential for viral rebound. The review discusses the molecular mechanisms that regulate HIV-1 transcription, including the role of host factors such as transcription initiation factors (NFAT, NF-κB), chromatin remodeling complexes (BAF, PBAF), and epigenetic silencing mechanisms. It emphasizes the importance of understanding the transitions between active effector cells and quiescent memory cells, which are not fully recapitulated in transformed cell models like Jurkat T-cells. Recent studies using primary cell models and ex vivo cellular systems have identified key factors that block HIV-1 transcription in memory CD4+ T cells, such as restrictive epigenetic features at the proviral promoter, cytoplasmic sequestration of transcription initiation factors, and low expression of the cellular transcription elongation factor P-TEFb. The "Shock and Kill" strategy, which aims to reactivate latent HIV-1 proviruses to clear persistently infected cells, is discussed, along with the need for effective latency-reversing agents (LRAs). The review also explores the dynamics of the HIV reservoir, including the clonal expansion of latently infected cells driven by homeostatic proliferation and antigen-mediated activation. It highlights the role of T-cell signaling mechanisms in stimulating P-TEFb biogenesis and reversing proviral epigenetic restrictions. Finally, the review delves into the chromatin organization of proviral HIV-1 and its epigenetic silencing, including the involvement of histone modifications, DNA methylation, and phase-separated nuclear condensates. It discusses the potential of epigenetic modifications to permanently silence HIV-1, as suggested by the "Block and Lock" strategy, and the challenges in achieving this goal. Keywords: HIV-1 latency, HIV-1 reservoir, Latency reversal, Epigenetic silencing, Transcription elongation, T-cell receptor signaling, P-TEFb, HIV-1 Tat, 7SK snRNP