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.
Highlights
25, FDA approved drugs are available for the treatment of Human Immunodeficiency virus (HIV)/AIDS, but there is currently no cure for this disease[1,2,3]
Virus production was measured by detecting expression of the HIV-1 capsid protein, p24 by western blotting
TEA, a broad-spectrum potassium channel blocker[35,36], reduced virus production by 90% (Fig. 2a,b). These observations suggest that potassium channels may play a vital role in the life cycle of HIV
Summary
25, FDA approved drugs are available for the treatment of HIV/AIDS, but there is currently no cure for this disease[1,2,3]. The K+ channels are broadly classified in two groups: voltage-gated and ligand-gated which are further classified in 4 subfamilies: voltage-gated K+ channels (KV), inwardly rectifying K+ channels (Kir), two-pore K+ channels (K2p) and calcium-activated K+ channels (BK)[14] These channels have been implicated to play a vital role during virus infection. Enveloped viruses such as Semliki forest virus and Human rhinovirus type 2 modulate membrane potential for their entry and release from the host cell by modulating host ion channels during their life cycle[15,16,17]. HIV-1 protein Nef alters the intracellular K+ ion concentration[30] by targeting large-conductance Ca2+-dependent K+ channels (BKCa)[31] whereas viral Env protein, gp[120] inhibits the voltage-gated K+ channel (BEC1) activity resulting in decreased virus release[32]. We propose that potassium channels may be further explored as new, pharmacologically safe HIV therapeutics
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