Abstract
Advancement in drug therapies and patient care have drastically improved the mortality rates of HIV-1 infected individuals. Many of these therapies were developed or improved upon by using structure-based techniques, which underscore the importance of understanding essential mechanisms in the replication cycle of HIV-1 at the structural level. One such process which remains poorly understood is the incorporation of the envelope glycoprotein (Env) into budding virus particles. Assembly of HIV particles is initiated by targeting of the Gag polyproteins to the inner leaflet of the plasma membrane (PM), a process mediated by the N-terminally myristoylated matrix (MA) domain and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). There is strong evidence that formation of the Gag lattice on the PM is a prerequisite for the incorporation of Env into budding particles. It is also suggested that Env incorporation is mediated by an interaction between its cytoplasmic tail (gp41CT) and the MA domain of Gag. In this review, we highlight the latest developments and current efforts to understand the interplay between gp41CT, MA, and the membrane during assembly. Elucidation of the molecular determinants of Gag–Env–membrane interactions may help in the development of new antiviral therapeutic agents that inhibit particle assembly, Env incorporation and ultimately virus production.
Highlights
Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immune deficiency syndrome (AIDS), is responsible for one of the deadliest viral pandemics in human history
Because HIV-1 still represents a major risk to human health and safety around the globe, it is vital that efforts continue to focus on new targets within the virus replication cycle
Subsequent to their synthesis, Gag polyproteins are targeted to the assembly sites on the inner leaflet of the plasma membrane (PM) for particle budding and release (Figure 1) [10,11,12,13,14,15,16]
Summary
Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immune deficiency syndrome (AIDS), is responsible for one of the deadliest viral pandemics in human history. While ARTs have been effective in combating the AIDS epidemic, they are not capable of eradicating the virus from the body entirely, requiring patients to undergo indefinite treatments [3]. Three-dimensional molecular structures often provide detailed information on biological mechanisms, which significantly aid in the development of therapeutic interventions [7]. The development of new drugs designed to disrupt the viral assembly process could enhance the effectiveness of modern treatment options or overcome issues of drug resistance and toxicity. This review will focus on illustrating the structure and function of essential elements involved in assembly and incorporation of the envelope (Env) protein into budding particles which are indispensable steps. Detailed molecular characterization of this key step may aid in the development of new therapeutic strategies that inhibit virus assembly and Env incorporation
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