Insights into the HIV Latency and the Role of Cytokines

Abstract

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.

Combinatorial Use of Both Epigenetic and Non-Epigenetic Mechanisms to Efficiently Reactivate HIV Latency

“…Molecular control and maintenance of HIV latency are mediated by multiple factors acting in concert, including epigenetic and non-epigenetic mechanisms [ 4 , 5 ]. HIV integration preferentially occurs within actively transcribed cellular genes [ 6 ].…”

“…Most of the latent or hibernating HIV proviruses are capable of entering into a fully productive lytic infection but await optimal conditions, that usually arise following the reactivation of quiescent memory CD4+ T-cells, which again make them metabolically active. However, the molecular control of HIV latency in resting memory CD4+ T-cells is multi-pronged [ 4 , 5 ], and effective and efficient reactivation of the latent HIV proviruses in all subsets of quiescent resting memory CD4+ T-cells requires a combinatorial approach involving both epigenetic and non-epigenetic mechanisms of HIV latency reactivation.…”

Efficient Non-Epigenetic Activation of HIV Latency through the T-Cell Receptor Signalosome

“…However, upon fulfillment of their effector functions, the activated CD4+ T-cells revert back to become quiescent resting memory CD4+ T-cells. Following the process of reversion back into quiescence, some of the quiescent resting memory CD4 T-cells that were infected as effector CD4+ T-cells then harbor the latent HIV proviruses, and this is the process through which HIV latency is established and maintained [ 7 ]. Subsequently, the reactivation of quiescent resting memory CD4+ T-cells following the encounter with the same antigen results in the activation of latent HIV proviruses from memory CD4+ T-cells due to the mobilization of the TCR-induced transcription factors and their translocation into the nucleus following the TCR activation.…”

Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

“…Acting through autocrine, paracrine, and endocrine mechanisms, endogenous immune stimuli maintain homeostasis and signal response to invasion, injury, or malignancy. Immune dysregulation underlies a broad set of human diseases including inflammation 1 , autoimmune disease 2 , neuroinflammation 3 , neurodegenerative disease 4 , secondary effects of traumatic brain injury 5 , cancer 6,7 , infection [8][9][10] , and cytokine storm 11,12 . Improvements in the understanding of how immune stimuli amplify or suppress the immune system, trigger new cell fate differentiation, and remodel tissue have resulted in the discovery of a wide range of successful therapeutics 13 , as demonstrated by the anti-TNF antibody adalimumab (Humira), noted both for its discovery 14 and its application in rheumatic disease 15 .…”