Kinases: Understanding Their Role in HIV Infection

Abstract

Antiviral drugs currently on the market primarily target proteins encoded by specific viruses. The drawback of these drugs is that they lack antiviral mechanisms that account for resistance or viral mutation. Thus, there is a pressing need for researchers to explore and investigate new therapeutic agents with other antiviral strategies. Viruses such as the human immunodeficiency virus (HIV) alter canonical signaling pathways to create a favorable biochemical environment for infectivity. We used Qiagen Ingenuity Pathway Analysis (IPA) software to review the function of several cellular kinases and the resulting perturbed signaling pathways during HIV infection such as NF-κB signaling. These host cellular kinases such as ADK, PKR, MAP3K11 are involved during HIV infection at various stages of the life cycle. Additionally IPA analysis indicated that these modified host cellular kinases are known to have interactions with each other especially AKT1, a serine/threonine kinase involved in multiple pathways. We present a list of cellular host kinases and other proteins that interact with these kinases. This approach to understanding the relationship between HIV infection and kinase activity may introduce new drug targets to arrest HIV infectivity.

Comparative Analysis of Differential Cellular Transcriptome and Proteome Regulation by HIV-1 and HIV-2 Pseudovirions in the Early Phase of Infection

“…Also, calcium/calmodulin-dependent protein kinase 1D (CAMK1D) was downregulated by HIV-1. The activity of CAMK1D was found to be negatively regulated by HIV-1 infection, which was in correlation with our results, wherein we observed decreased mRNA levels [ 37 ]. It was also shown that siRNA knockdown of CAMK1D can inhibit HIV-1 infection [ 38 ].…”

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

“…Among the potential signaling pathways often targeted by retroviruses, ERVK IN-associated cascades emerged as Forkhead box O (FoxO) signaling [ 75 ], p53 signaling [ 76 ], ErbB signaling [ 77 ], Wnt signaling [ 78 ], modulation of kinase activity [ 79 , 80 ], and multiple aspects of immune signaling [ 81 ] ( Figure 4 ). Within these pathways, prominent immune-related signaling intermediates included STAT3 [ 55 ], STAT5 [ 56 ], and TRAF2 [ 82 ].…”

Inhibition of salt inducible kinases reduces rhythmic HIV-1 replication and reactivation from latency

“…A previous report identified Sik1 in an ingenuity pathway analysis of kinases regulating HIV-1, however, it was not studied further [21]. Our experimental study illustrates that SIK inhibitors perturb the cellular circadian clock, reduce rhythmic HIV-1 replication and inhibit viral replication in primary T Pharmacological and genetic disruption of SIKs reduced TNFα mediated reactivation of HIV-1 in the J-Lat T cell model, altogether highlighting a pro-viral role for SIKs in regulating HIV-1 infection.…”

“…A previous report identified Sik1 in an ingenuity pathway analysis of kinases regulating HIV-1, however, it was not studied further [ 21 ]. Our experimental study illustrates that SIK inhibitors perturb the cellular circadian clock, reduce rhythmic HIV-1 replication and inhibit viral replication in primary T cells.…”

“…The CRTC1-SIK1 pathway regulates entrainment of circadian rhythms by suppressing the effects of light on clock [19] and SIK3 was shown to destabilise the core circadian factor Period 2 (PER2) [20]. Various kinases have been reported to regulate HIV-1 infection [21,22], however, the interplay of SIKs and HIV-1 has not been studied to date. We hypothesised that SIKs regulate rhythmic HIV-1 replication and latency reactivation and tested this by pharmacological inhibition, as well as transient siRNA silencing of Sik expression in vitro.…”