Structural analysis and molecular dynamics simulation studies of HIV-1 antisense protein predict its potential role in HIV replication and pathogenesis

Abstract

The functional significance of the HIV-1 Antisense Protein (ASP) has been a paradox since its discovery. The expression of this protein in HIV-1-infected cells and its involvement in autophagy, transcriptional regulation, and viral latency have sporadically been reported in various studies. Yet, the definite role of this protein in HIV-1 infection remains unclear. Deciphering the 3D structure of HIV-1 ASP would throw light on its potential role in HIV lifecycle and host-virus interaction. Hence, using extensive molecular modeling and dynamics simulation for 200 ns, we predicted the plausible 3D-structures of ASP from two reference strains of HIV-1 namely, Indie-C1 (subtype-C) and NL4-3 (subtype-B) so as to derive its functional implication through structural domain analysis. In spite of sequence and structural differences in subtype B and C ASP, both structures appear to share common domains like the Von Willebrand Factor Domain-A (VWFA), Integrin subunit alpha-X (ITGSX), and ETV6-Transcriptional repressor, thereby reiterating the potential role of HIV-1 ASP in transcriptional repression and autophagy, as reported in earlier studies. Gromos-based cluster analysis of the centroid structures also reassured the accuracy of the prediction. This is the first study to elucidate a highly plausible structure for HIV-1 ASP which could serve as a feeder for further experimental validation studies.

Origin and functional role of antisense transcription in endogenous and exogenous retroviruses

“…Thorough and systematic experimental analyses are needed to assess the functional role of these and possibly other yet unidentified ASP domains [ 50 ]. A very recent study utilized molecular modeling and dynamics simulation to predict the 3D-structures of ASP [ 51 ]. The in silico analyses described in that study identified three possible functional domains in ASP, namely the Von Willebrand Factor Domain-A (VWFA), the Integrin subunit alpha-X (ITGSX), and the ETV6-Transcriptional repressor [ 51 ].…”

“…A very recent study utilized molecular modeling and dynamics simulation to predict the 3D-structures of ASP [ 51 ]. The in silico analyses described in that study identified three possible functional domains in ASP, namely the Von Willebrand Factor Domain-A (VWFA), the Integrin subunit alpha-X (ITGSX), and the ETV6-Transcriptional repressor [ 51 ]. Wet lab molecular studies are required to confirm the validity of these findings, and to ascertain the role these domains play in the mechanisms of action of ASP.…”