G protein-coupled and ATP-sensitive inwardly rectifying potassium ion channels are essential for HIV entry

Abstract

The high genetic diversity of Human Immunodeficiency virus (HIV), has hindered the development of effective vaccines or antiviral drugs against it. Hence, there is a continuous need for identification of new antiviral targets. HIV exploits specific host proteins also known as HIV-dependency factors during its replication inside the cell. Potassium channels play a crucial role in the life cycle of several viruses by modulating ion homeostasis, cell signaling, cell cycle, and cell death. In this study, using pharmacological tools, we have identified that HIV utilizes distinct cellular potassium channels at various steps in its life cycle. Members of inwardly rectifying potassium (Kir) channel family, G protein-coupled (GIRK), and ATP-sensitive (KATP) are involved in HIV entry. Blocking these channels using specific inhibitors reduces HIV entry. Another member, Kir 1.1 plays a role post entry as inhibiting this channel inhibits virus production and release. These inhibitors are not toxic to the cells at the concentration used in the study. We have further identified the possible mechanism through which these potassium channels regulate HIV entry by using a slow-response potential-sensitive probe DIBAC4(3) and have observed that blocking these potassium channels inhibits membrane depolarization which then inhibits HIV entry and virus release as well. These results demonstrate for the first time, the important role of Kir channel members in HIV-1 infection and suggest that these K+ channels could serve as a safe therapeutic target for treatment of HIV/AIDS.

Ontological and Bioinformatic Analysis of Anti-Coronavirus Drugs and Their Implication for Drug Repurposing against COVID-19

“…In addition to azithromycin, our study found other antibiotics, including teicoplanin, anisomycin (Dyall et al, 2014), valinomycin (Dubey et al, 2019), which demonstrated anticoronavirus functions in vitro and/or in vivo (Table 1) well (Zhou et al, 2016). Valinomycin is a K + ionophore that can change the membrane potential by conducting ions directly through membrane.…”

“…It can treat B. gibsoni, a species of bacterial infection, by changing bacteria's cellular cation concentration in vitro (Yamasaki et al, 2009). In a study, TZMbl cells were treated with valinomycin before HIV infection, and valinomycin at 10 nM concentration impeded HIV entry to TZMbl cells by nearly 50% (Dubey et al, 2019). The study also showed that valinomycin inhibits HIV entry by increasing the membrane depolarization, which indicates membrane polarization is crucial for HIV entry.…”

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

“…Recent work also highlights a requirement for K + channels during human immunodeficiency virus (HIV) infection. Using pharmacological approaches ( Figure 1 A) [ 40 ] HIV entry could be blocked with ifenprodil and the broad spectrum K + channel blocker tetraethylammonium (TEA). Khan et al also showed that the pharmacological activation of the endolysosome-resident transient receptor potential mucolipin 1 channel (TRPML1) enhanced the degradation of HIV-Tat (a multi-function viral protein involved in transcription, splicing, capping, and translation), which in turn reduced the transition from viral latency [ 52 ].…”

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

“…Emerging studies suggest that the current description of virus entry processes involving acidification alone are too simplistic and that the accumulation of other ions including K + and Ca 2+ influence virus trafficking (38–43). In the context of PyV infection, Ca 2+ ions have been shown to affect the structure and organisation of virus particles, regulating their disassembly through virion swelling (40, 44–46).…”

“…In the context of PyV infection, Ca 2+ ions have been shown to affect the structure and organisation of virus particles, regulating their disassembly through virion swelling (40, 44–46). However, despite the evidence that cellular ion channels are targeted by a wide range of viruses to enhance specific lifecycle stages, their role during PyV entry has not been defined (40, 41, 53, 42, 43, 47–52).…”