Hokello Joseph, Sharma Adhikarimayum Lakhikumar, Dimri Manjari, Tyagi Mudit
Department of Basic Science, Kampala International University-Western Campus, Faculty of Science and Technology, Bushenyi, Uganda.
Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
Pathogens. 2019 Sep 4;8(3):137. doi: 10.3390/pathogens8030137.
Human immunodeficiency virus-1 (HIV-1) has the ability to infect latently at the level of individual CD4+ cells. Latent HIV-1 proviruses are transcriptionally silent and immunologically inert, but are still capable of reactivating productive lytic infection following cellular activation. These latent viruses are the main obstacle in the eradication of HIV-1, because current HIV-1 treatment regimens are ineffective against them. Normal immunological response against an antigen activates CD4+ naïve T cells. The activated CD4+ naïve T cells undergo cell cycle, resulting in further transformation and profound proliferation to form effector CD4+ T-cells. Notably, in HIV-1 infected individuals, some of the effector CD4+ T cells get infected with HIV-1. Upon fulfillment of their effector functions, almost all activated CD4+ T cells are committed to apoptosis or programmed cell death, but a miniscule fraction revert to quiescence and become resting memory CD4+ T cells to mediate a rapid immunological response against the same antigen in the future. However, due to the quiescent nature of the resting memory T cells, the integrated HIV-1 becomes transcriptionally silent and acquires a latent phenotype. Following re-exposure to the same antigen, memory cells and integrated HIV-1 are stimulated. The reactivated latent HIV provirus subsequently proceeds through its life cycle and eventually leads to the production of new viral progeny. Recently, many strategies against HIV-1 latency have been developed and some of them have even matured to the clinical level, but none can yet effectively eliminate the latent HIV reservoir, which remains a barrier to HIV-1 cure. Therefore, alternative strategies to eradicate latent HIV need to be considered. This review provides vital knowledge on HIV latency and on strategies to supplement highly active anti-retroviral therapy (HAART) with cytokine-mediated therapeutics for dislodging the latent HIV reservoirs in order to open up new avenues for curing HIV.
人类免疫缺陷病毒1型（HIV-1）能够在个体CD4+细胞水平上进行潜伏感染。潜伏的HIV-1前病毒转录沉默且免疫惰性，但在细胞激活后仍能够重新激活产生有活性的裂解感染。这些潜伏病毒是根除HIV-1的主要障碍，因为目前的HIV-1治疗方案对它们无效。针对抗原的正常免疫反应会激活CD4+初始T细胞。被激活的CD4+初始T细胞进入细胞周期，导致进一步转化和大量增殖，形成效应CD4+T细胞。值得注意的是，在HIV-1感染个体中，一些效应CD4+T细胞会被HIV-1感染。在完成效应功能后，几乎所有激活的CD4+T细胞都会走向凋亡或程序性细胞死亡，但极小一部分会恢复静止状态，成为静止记忆CD4+T细胞，以便在未来介导针对同一抗原的快速免疫反应。然而，由于静止记忆T细胞的静止特性，整合的HIV-1转录沉默并获得潜伏表型。再次接触相同抗原后，记忆细胞和整合的HIV-1会被激活。重新激活的潜伏HIV前病毒随后进入其生命周期，最终导致产生新的病毒后代。最近，已经开发出许多针对HIV-1潜伏的策略，其中一些甚至已经发展到临床阶段，但尚无一种能够有效消除潜伏的HIV储存库，这仍然是治愈HIV-1的障碍。因此，需要考虑根除潜伏HIV的替代策略。本综述提供了关于HIV潜伏以及用细胞因子介导的疗法补充高效抗逆转录病毒疗法（HAART）以清除潜伏HIV储存库的策略的重要知识，以便为治愈HIV开辟新途径。
