Abstract
While significant progress has been made in terms of human immunodeficiency virus (HIV) therapy, treatment does not represent a cure and remains inaccessible to many people living with HIV. Continued mechanistic research into the viral life cycle and its intersection with many aspects of cellular biology are not only fundamental in the continued fight against HIV, but also provide many key observations of the workings of our immune system. Decades of HIV research have testified to the integral role of the actin cytoskeleton in both establishing and spreading the infection. Here, we review how the virus uses different strategies to manipulate cellular actin networks and increase the efficiency of various stages of its life cycle. While some HIV proteins seem able to bind to actin filaments directly, subversion of the cytoskeleton occurs indirectly by exploiting the power of actin regulatory proteins, which are corrupted at multiple levels. Furthermore, this manipulation is not restricted to a discrete class of proteins, but rather extends throughout all layers of the cytoskeleton. We discuss prominent examples of actin regulators that are exploited, neutralized or hijacked by the virus, and address how their coordinated deregulation can lead to changes in cellular behavior that promote viral spreading.
Highlights
Actin is the most abundant protein in human cells and is essential for a wide range of cellular processes [1], including transport of cargo and maintenance of cellular architecture
We hypothesize that selective upregulation of focal adhesion proteins in productively human immunodeficiency virus (HIV)-infected cells might promote outbound virus spread, whereas in uninfected cells, they might serve as restriction factors for inbound
In contrast to the fine-tuned manipulation of cofilin by inbound HIV via envelope glycoprotein (Env) (Figure 2), productively infected cells seem to display a broad neutralization of cofilin activity, which is mainly mediated by Nef
Summary
Actin is the most abundant protein in human cells and is essential for a wide range of cellular processes [1], including transport of cargo and maintenance of cellular architecture. We define “outbound virus” as the collection of viral components which are produced de novo in an infected cell and which are in the process of exiting this cell in the form of initially immature HIV particles This includes viral proteins and RNA during their transport to the PM, particle assembly and budding, up to the point of abscission. A third scenario is given by soluble viral proteins such as Tat, Env and Nef, which are known to be present extracellularly, as well as inside uninfected cells both in vitro and in vivo [26,27,28] These soluble factors can induce cytoskeletal changes in a broad range of cells, including cell types that are not typically infected by HIV. Our definition of inbound and outbound HIV extends to both cell-free and cell-cell transmitted virus
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