Gag-Gag Interactions Are Insufficient to Fully Stabilize and Order the Immature HIV Gag Lattice.

Ipsita Saha,Saveez Saffarian,David Belnap,Michael Vershinin,Jake Lowe,Brian Macarthur,Abby Peterson,Benjamin Preece,Haley Durden

doi:10.3390/v13101946

Ipsita Saha, Saveez Saffarian + Show 7 more

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https://doi.org/10.3390/v13101946

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Abstract

Immature HIV virions harbor a lattice of Gag molecules with significant ordering in CA-NTD, CA-CTD and SP1 regions. This ordering plays a major role during HIV maturation. To test the condition in which the Gag lattice forms in vivo, we assembled virus like particles (VLPs) by expressing only HIV Gag in mammalian cells. Here we show that these VLPs incorporate a similar number of Gag molecules compared to immature HIV virions. However, within these VLPs, Gag molecules diffuse with a pseudo-diffusion rate of 10 nm2/s, this pseudo-diffusion is abrogated in the presence of melittin and is sensitive to mutations within the SP1 region. Using cryotomography, we show that unlike immature HIV virions, in the Gag lattice of VLPs the CA-CTD and SP1 regions are significantly less ordered. Our observations suggest that within immature HIV virions, other viral factors in addition to Gag, contribute to ordering in the CA-CTD and SP1 regions.

Highlights

Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS)
It is a common view that the immature HIV Gag lattice is a critical starting point for maturation and interactions which result in stabilization of the immature lattice, including the cellular cofactor IP6 have been of great interest [12,13,14]
We show significant evidence that Gag molecules assembled into virus like particles (VLPs) incorporating similar numbers of Gag molecules to HIV virions, fail to create a stable Gag lattice

Summary

Introduction

Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV-1 virions are released from infected cells as immature virions, mainly characterized by a lattice of HIV Gag proteins anchored to the inner leaflet of the virion membrane. During maturation, this lattice is transformed by successive actions of the 22 kD HIV protease dimer [2,3]. Most of the antivirals available for treatment result in abnormalities in the formation of the mature core. Protease inhibitors result in lack of proteolysis trapping the lattice in the immature form [6] and maturation inhibitors result in formation of aberrant cores [1,7,8]. It is a common view that the immature HIV Gag lattice is a critical starting point for maturation and interactions which result in stabilization of the immature lattice, including the cellular cofactor IP6 have been of great interest [12,13,14]

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