The cell biology of HIV-1 latency and rebound HIV-1 latency is a major barrier to a cure for HIV-1 infection, as it is the source of viral rebound following the interruption of antiretroviral therapy. Latent HIV-1 proviruses are primarily found in a small subset of memory CD4+ T cells. Over the past 30 years, many factors essential for initiating HIV-1 transcription have been identified in studies using transformed cell lines, such as the Jurkat T-cell model. However, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP. The central paradox of HIV-1 transcription remains unsolved: how are the initial rounds of transcription achieved in the absence of Tat? A critical limitation of the transformed cell models is that they do not recapitulate the transitions between active effector cells and quiescent memory T cells. Therefore, investigation of the molecular mechanisms of HIV-1 latency reversal and LRA efficacy in a proper physiological context requires the utilization of primary cell models. Recent mechanistic studies of HIV-1 transcription using latently infected cells recovered from donors and ex vivo cellular models of viral latency have demonstrated that the primary blocks to HIV-1 transcription in memory CD4+ T cells are restrictive epigenetic features at the proviral promoter, the cytoplasmic sequestration of key transcription initiation factors such as NFAT and NF-κB, and the vanishingly low expression of the cellular transcription elongation factor P-TEFb. One of the foremost schemes to eliminate the residual reservoir is to deliberately reactivate latent HIV-1 proviruses to enable clearance of persisting latently infected cells—the "Shock and Kill" strategy. For "Shock and Kill" to become efficient, effective, non-toxic latency-reversing agents (LRAs) must be discovered. Since multiple restrictions limit viral reactivation in primary cells, understanding the T-cell signaling mechanisms that are essential for stimulating P-TEFb biogenesis, initiation factor activation, and reversing the proviral epigenetic restrictions have become a prerequisite for the development of more effective LRAs. Keywords: HIV-1 latency, HIV-1 reservoir, Latency reversal, Epigenetic silencing, Transcription elongation, T-cell receptor signaling, P-TEFb, HIV-1 Tat, 7SK snRNP In untreated people with HIV (PWH), the unabated replication of HIV-1 in CD4+ T cells allows the virus to evade adaptive immune responses through rapid evolution, eventually leading to the profound depletion of these cells and susceptibility to opportunistic infections (AIDS). Combination antiretroviral regimens (ART), first introduced in the late 1990s, are remarkably effectiveThe cell biology of HIV-1 latency and rebound HIV-1 latency is a major barrier to a cure for HIV-1 infection, as it is the source of viral rebound following the interruption of antiretroviral therapy. Latent HIV-1 proviruses are primarily found in a small subset of memory CD4+ T cells. Over the past 30 years, many factors essential for initiating HIV-1 transcription have been identified in studies using transformed cell lines, such as the Jurkat T-cell model. However, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP. The central paradox of HIV-1 transcription remains unsolved: how are the initial rounds of transcription achieved in the absence of Tat? A critical limitation of the transformed cell models is that they do not recapitulate the transitions between active effector cells and quiescent memory T cells. Therefore, investigation of the molecular mechanisms of HIV-1 latency reversal and LRA efficacy in a proper physiological context requires the utilization of primary cell models. Recent mechanistic studies of HIV-1 transcription using latently infected cells recovered from donors and ex vivo cellular models of viral latency have demonstrated that the primary blocks to HIV-1 transcription in memory CD4+ T cells are restrictive epigenetic features at the proviral promoter, the cytoplasmic sequestration of key transcription initiation factors such as NFAT and NF-κB, and the vanishingly low expression of the cellular transcription elongation factor P-TEFb. One of the foremost schemes to eliminate the residual reservoir is to deliberately reactivate latent HIV-1 proviruses to enable clearance of persisting latently infected cells—the "Shock and Kill" strategy. For "Shock and Kill" to become efficient, effective, non-toxic latency-reversing agents (LRAs) must be discovered. Since multiple restrictions limit viral reactivation in primary cells, understanding the T-cell signaling mechanisms that are essential for stimulating P-TEFb biogenesis, initiation factor activation, and reversing the proviral epigenetic restrictions have become a prerequisite for the development of more effective LRAs. Keywords: HIV-1 latency, HIV-1 reservoir, Latency reversal, Epigenetic silencing, Transcription elongation, T-cell receptor signaling, P-TEFb, HIV-1 Tat, 7SK snRNP In untreated people with HIV (PWH), the unabated replication of HIV-1 in CD4+ T cells allows the virus to evade adaptive immune responses through rapid evolution, eventually leading to the profound depletion of these cells and susceptibility to opportunistic infections (AIDS). Combination antiretroviral regimens (ART), first introduced in the late 1990s, are remarkably effective