Protein-Protein interactions (PPI) are instrumental to operate most biological processes regulating all types of cellular functions. Similarly, Virus-host protein interactions are obligatory to hijack all physiological pathways in the host in their favour for production of new virons. HIV belongs to the retroviridae family of genome size 9.2 Kb expressing fifteen proteins and most of them interact with host proteins to rearrange cellular pathways for successful completion of the viral life cycle. The virus-host protein interactions have been considered to be novel targets for developing anti-viral therapeutics.
There are several drugs developed against different target proteins of HIV which can control but cannot cure the HIV pathogenesis. I picked HIV-1 Nef protein hypothesizing that this protein has the potential to cure HIV pathogenesis. Therefore, since 2002 my lab has been working on the identification of novel Nef-host protein interactions regulating cellular pathways for viral replication and on exploiting said interactions to develop inhibitors that could be developed as therapeutics as an alternative therapy to treat HIV-1 pathogenesis.
My laboratory has not only identified more than five novel host proteins interacting with Nef but has also identified specific cellular pathways regulated through these interactions. Moreover, the multiprotein complex assembled in response to the Nef-host protein interaction has been deciphered in regulating different cellular functions like immune evasion, apoptosis and protein transport pathways. Our group has solved Nef multimeric protein structure showing cytosolic localization in cells and the putative domains accessible for host protein interactions enabling to design inhibitors that disrupt interactions, restoring cellular functions regulating pathogenesis.
With the experience in the virus-host protein interaction area, we have extended our studies to understand SARS-CoV-2 and Japanese Encephalitis Virus (JEV) capsid protein function in the viral life cycle. The capsid is a structural protein whose function is to protect newly synthesized viral transcripts by packaging them into nucleocapsid complex. The molecular mechanism involved in nucleocapsid complex assembly is not fully understood.
Presently, my lab is working on identifying novel host proteins that can interact with capsid protein and identify interaction-mediated specific cellular pathways which could be regulating the important event in the viral life cycle, formation of nucleoprotein complex and assembly of virus proteins for new viron release. The molecular characterization of host protein involved in the formation of nucleoprotein complex and assembly will be characterized by implying knock-out and knock-down strategies using Crisper-Cas9 and SiRNA molecular techniques. The development of inhibitors disrupting the capsid-host protein interactions would interfere with important stages of virus assembly reducing viral pathogenesis could become a novel target for developing anti-viral therapeutics.
Our research work majorly focuses on the following aspects:
1) Identification and functional characterization of HIV-1 Nef interacting candidate protein in immune and neuronal cells.
2) Identification and functional characterization of interacting candidate host protein with SARS CoV-2 and JEV capsid proteins: Blocking of host-virus interaction with effective inhibitors.
3) Identification and characterization of interacting doamins of JEV capsid proteins assisting in the production of new virons.