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Review
. 2018 Sep 11:9:2131.
doi: 10.3389/fmicb.2018.02131. eCollection 2018.

Post-translational Modification-Based Regulation of HIV Replication

Lin Chen  1 , Oliver T Keppler  1 , Christian Schölz  1
Affiliations
Review

Post-translational Modification-Based Regulation of HIV Replication

Lin Chen et al. Front Microbiol. .

Abstract

Human immunodeficiency virus (HIV) relies heavily on the host cellular machinery for production of viral progeny. To exploit cellular proteins for replication and to overcome host factors with antiviral activity, HIV has evolved a set of regulatory and accessory proteins to shape an optimized environment for its replication and to facilitate evasion from the immune system. Several cellular pathways are hijacked by the virus to modulate critical steps during the viral life cycle. Thereby, post-translational modifications (PTMs) of viral and cellular proteins gain increasingly attention as modifying enzymes regulate virtually every step of the viral replication cycle. This review summarizes the current knowledge of HIV-host interactions influenced by PTMs with a special focus on acetylation, ubiquitination, and phosphorylation of proteins linked to cellular signaling and viral replication. Insights into these interactions are surmised to aid development of new intervention strategies.

Keywords: HIV; HIV life cycle; PTM; post-translational modification; viral replication.

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Figures

FIGURE 1
FIGURE 1
HIV-related PTMome – an overview. (A) Schematic illustration of protein modifications discussed in this review. Proteins can be modified by different enzymes, which either introduce a functional group (“writers”) or remove it (“erasers”). Thereby, lysine acetylation is achieved by lysine-acetyltransferases (KATs) and the backward reaction is fulfilled by lysine deacetylases (KDACs, also known as histone deacetylases (HDACs)) or sirtuins. Lysines can be also modified by ubiquitin in presence of E1 ubiquitin-activating-, E2 ubiquitin-conjugating-enzymes, and E3 ubiquitin ligases. Reversal of ubiquitin linkages is achieved by deubiquinating enzymes (DUBs). Another frequent modification occurs at serine-/threonine- and/or tyrosine-residues, where phosphate groups are transferred to by kinases. Removal of phosphorylation is carried out by phosphatases. All three modifications can influence each other and might occur at the same protein. (B) HIV interacts with several modifying enzymes. Based on the NCBI HIV interaction database, several interactions of viral proteins with modifying enzymes have been described. Shown here are six groups of writers and erasers, which interact in one way or another with HIV during the viral lifecycle. The graph provides the percentage (number in circle) of interacting enzymes of a respective class in comparison to the amount of enzymes of the same class found in the human proteome. Number of all enzymes of a class is given on the right site and is based on the HNGC database, the National Heart Lung and Blood Institute ESBL human E3 ubiquitin ligases databank, The Ubiquitin and Ubiquitin-like Conjugation Database (UUCD), and databases for protein kinases2 and phosphatases (DEPOD)3. Notably, for acetylation not only lysine-acetyltransferases but also N-terminal acetyltransferases were included. (C) Schematic overview of viral proteins interacting with modifying enzymes. The graph depicts the number of interactions of different HIV proteins with kinases/phosphatases, KATs/KDACs, and E3 ligases/DUBs. Number of interactions is provided in form of a heat map.
FIGURE 2
FIGURE 2
Interaction networks of HIV and host proteins during early steps of infection. (A) Binding of HIV to the host cell. Binding of the viral envelope GP160 complex, consisting of GP120 and GP41, to CD4 as well as the co-receptors CXCR4 or CCR5 results in activation of several protein kinases. Thereby, the cytoskeleton becomes rearranged, which favors entry and subsequent nuclear import of the virus. The network displays an overview of relevant interactions. Black arrows indicate activating effects and red “inhibitory”-arrows indicate inhibitory effects. Kinases are depicted in dark blue, phosphatases in light blue, KATs in dark red, KDACs in light red, E3 ligases in dark yellow, and DUBs in light yellow. Other host proteins are colored white, whereas viral proteins are presented in gray. (B) Uncoating and reverse transcription. The graph illustrates several protein-protein interactions that have been described during uncoating and reverse transcription. Please note that VPX is only expressed in HIV-2 and SIV but not in HIV-1. CRL4 complex consists of cullin4A (CUL4A), DNA damage binding protein 1 (DDB1), RING H2 finger protein (RBX1) and the DDB1 and CUL4-associated Factor 1 (DCAF1). Figure legend as in A. More detailed information can be found in the text.
FIGURE 3
FIGURE 3
Nuclear import and genomic integration. The graphic illustrates the influence of post-translational modifying enzymes on the nuclear transport of the PIC and the integration of the viral cDNA into the host genome. Figure legend as in Figure 2A. More detailed information can be found in the text.
FIGURE 4
FIGURE 4
Transcription and latency. (A) The interaction scheme displays protein-protein interactions that have been identified to promote transcription of viral genes. (B) Likewise, to A, the protein network demonstrates the influence of modifying enzymes onto the latent state of HIV. Figure legend as in Figure 2A. Additionally, methyl-transferases, depicted in green, are shown. More detailed information can be found in the text.
FIGURE 5
FIGURE 5
Viral protein translation and virus assembly. The interaction network visualizes processes, which are accompanied with the late steps of HIV infection and the formation of new virions. Figure legend as in Figure 2A. More detailed information can be found in the text.
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