Subtype Differences in the Interaction of HIV-1 Matrix with Calmodulin: Implications for Biological Functions.

Alexej Dick,Simon Cocklin

doi:10.3390/biom11091294

Abstract

The HIV-1 Gag polyprotein plays essential roles during the late stage of the HIV-1 replication cycle, and has recently been identified as a promising therapeutic target. The N-terminal portion of the HIV-1 Gag polyprotein encodes the myristoylated matrix (MA) protein, which functions in the trafficking of the structural proteins to the plasma membrane (PM) and facilitation of envelope incorporation into budding virus. Numerous host cell proteins interact with the MA portion of the Gag polyprotein during this process. One such factor is the ubiquitous calcium-binding protein calmodulin (CaM), which interacts preferentially with myristoylated proteins, thereby regulating cell physiology. The exact role of this interaction is poorly understood to date. Atomic resolution structures revealed the nature of the CaM-MA interaction for clade B isolates. In this study, we expanded our knowledge and characterized biophysically and computationally the CaM interaction with MA from other HIV-1 clades and discovered differences in the CaM recognition as compared to the prototypical clade B MA, with significant alterations in the interaction with the MA protein from clade C. Structural investigation and in silico mutational analysis revealed that HIV-1 MA protein from clade C, which is responsible for the majority of global HIV-1 infections, interacts with lower affinity and altered kinetics as compared to the canonical clade B. This finding may have implications for additional altered interaction networks as compared to the well-studied clade B. Our analysis highlights the importance of expanding investigations of virus-host cell factor interaction networks to other HIV-1 clades.

Highlights

AIDS (Acquired Immune Deficiency Syndrome) is a global epidemic caused by two related lentiviruses, HIV-1 and the less pathogenic HIV-2 [1]
We collectively found that hCaM-1 interaction in vitro differs between clades with clade C MA displaying the lowest affinity towards hCaM-1 accompanied by a decreased on-rate compared to other clades
The N-terminal region of HIV-1 MA is crucial for multiple HIV-1 Gag functions, including membrane interaction via myristate exposure, binding to several host factors to facilitate Gag trafficking, and gp160 incorporation [9,39,40,41,42]

Summary

Introduction

AIDS (Acquired Immune Deficiency Syndrome) is a global epidemic caused by two related lentiviruses, HIV-1 and the less pathogenic HIV-2 [1]. At the end of 2019, 38 million people lived with HIV worldwide, with 1.7 million newly infected and 690.000 AIDS-related deaths [2]. These statistics highlight the continued need for novel antiviral agents and new therapeutic targets to combat acquired and naturally occurring resistance and the toxicity problems of current therapeutics. One such emerging therapeutic target is the HIV-1 Gag protein and its component domains [3]. Considerable effort has been expended upon targeting the HIV-1 CA protein, the nucleocapsid, as well as late domains (p6), and only a few studies have looked at the potential of the HIV-1 MA protein (reviewed in [3])

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