Research Article: HIV-1 Accessory Proteins Adapt Cellular Adaptors to Facilitate Immune Evasion

Date Published: January 23, 2014

Publisher: Public Library of Science

Author(s): David R. Collins, Kathleen L. Collins, Vincent Racaniello.


Partial Text

As obligate intracellular parasites, viruses must gain entry into target cells and utilize the host cellular machinery for production of viral progeny. After entering the cell and localizing to an intracellular niche, the virus sheds its capsid, replicates its genome, transcribes its RNA, translates its protein components, and assembles the components to form new progeny virions that can infect new cells. At each stage of the virus life cycle, the host has evolved mechanisms to restrict successful infection, and pathogenic viruses have evolved countermechanisms to overcome each restriction. This article will focus on the mechanisms by which the lentivirus human immunodeficiency virus type 1 (HIV-1) overcomes these barriers to establish and propagate infection in human cells.

While all retroviruses encode proteins required for entry, reverse transcription, integration into host DNA, protein processing, capsid formation, and genome packaging (Env, Pol, and Gag); more complex retroviruses of the lentivirus family, including HIV-1, encode several additional genes. Two of these genes encode proteins that regulate transcription and mRNA nuclear export (Tat and Rev respectively). The remaining genes (nef, vif, vpu, vpr, and/or vpx) encode “accessory proteins” that are not always required for viral infection in in vitro cell culture systems. Instead, these proteins enable pathogenesis in vivo by allowing lentiviruses to evade antiviral responses. Accessory proteins presumably evolved their functions under the selective pressures of continual replication in primate hosts, with each factor serving at least one specific role to enhance viral fitness. Decades of HIV-1 research have led to several key breakthroughs in our understanding of the specific activities and functions of accessory proteins. Interestingly, each accessory protein functions as an adaptor between two or more known host cellular proteins. In this way, the viral pathogen succeeds in dramatically enhancing its capacity to alter the host environment while minimizing its genome size.

To establish a successful infection, intracellular pathogens must evade CTLs, which recognize foreign antigens presented in association with host major histocompatibility complex class I (MHC-I). One way that HIV-1 achieves this goal is through the activity of the accessory protein negative effector factor (Nef). Nef enhances the survival of infected cells in the presence of CTLs by mislocalizing and degrading MHC-I [1], [2]. To accomplish this, Nef stabilizes an interaction between MHC-I and the clathrin adaptor protein-1 (AP-1), which regulates clathrin-dependent trafficking of proteins between the trans-Golgi network and endosomes. When stabilized in this complex by Nef, AP-1 directs MHC-I to the endolysosomal pathway where it is degraded at an accelerated rate [3]. Biochemical and structural analysis have revealed that a critical tyrosine residue in the MHC-I cytoplasmic tail mediates the interaction with the tyrosine-binding pocket in the µ1 subunit of AP-1 [4]–[6] (Figure 1A). While this tyrosine can weakly bind AP-1 in some cell types [7], a complex containing MHC-I and AP-1 is normally not detected in T lymphocytes. This is primarily because the MHC-I cytoplasmic tail tyrosine does not conform to a canonical AP-1 tyrosine signal in which there is a downstream hydrophobic amino acid (Yxxφ). Nef stabilizes the weak interaction between MHC-I and AP-1 by providing additional contacts with AP-1 and with the MHC-I cytoplasmic tail. Specifically, an acidic cluster in Nef forms an electrostatic interaction with positively charged residues of AP-1 µ1 [6]. In addition, polyproline (PxxP) repeats in Nef lock the MHC-I cytoplasmic tail onto µ1 (Figure 1) [6].

Ubiquitination is a post-translational protein modification that regulates protein degradation and trafficking. Cellular E3 ubiquitin ligases facilitate the transfer of ubiquitin from E2 ubiquitin-conjugating enzymes to lysine, serine, or threonine residues on specific target proteins. E3 ligases often comprise multi-protein complexes that include a scaffold, an adaptor, and a target protein substrate. By serving as substrate adaptors that simultaneously interact with ubiquitin ligase adaptors and cellular target proteins, three HIV accessory proteins (Vif, Vpu, and Vpr) induce ubiquitination of host targets. This leads to proteasomal degradation and/or mislocalization of targeted host proteins. For example, viral infectivity factor (Vif), an accessory protein encoded by primate lentiviruses, including HIV-1, counteracts the antiviral activities of apolipoprotein B mRNA editing complex 3 (APOBEC3, or A3) proteins, especially APOBEC3G (A3G) [12]. A3 deaminases, which attack single-stranded DNA converting cytidine to uridine, have broad antiviral functions (reviewed in [13]). In the absence of Vif, A3G-mediated cytidine deamination results in uridination of the first strand of DNA synthesized by the viral reverse transcriptase. Guanosine-to-adenosine hypermutation results as uridine residues are paired with adenosine upon second strand synthesis. There is also evidence that A3G has a separate inhibitory effect on the processivity of reverse transcription (reviewed in [13]). In HIV-1-infected T cells, A3G activity can induce a DNA damage response that stimulates up-regulation of natural killer (NK) cell-activating ligands on the surface of the infected cells and activates NK cell lysis of infected cells [14]. To evade A3-mediated responses, the HIV-1 Vif protein simultaneously binds A3G and the ubiquitin ligase adaptor EloBC, causing polyubiquitination by the Rbx2/Cullin5 E3 ubiquitin ligase complex (Figure 2A) [15]. An additional cellular protein, core binding factor β (CBF-β), stabilizes the formation of this complex [16], [17]. By driving the ubiquitin-dependent degradation of A3 family members, Vif enables viral escape from A3-mediated antiviral restriction. The critical importance of A3G as a cellular factor that restricts lentiviruses is evidenced by coevolution of Vif and A3G sequences [18].

The continual battle between host and virus provides constant selective pressure that shapes the viral genome. Research focused on the specific interactions that have evolved between lentiviral accessory proteins and their cellular targets has led to the identification and characterization of several antiviral factors (A3G, BST-2, and SAMHD1) and has informed our understanding of MHC-I trafficking pathways. Importantly, these host factors have broad and significant antiviral effects that can restrict a diverse array of viruses in addition to lentiviruses. The study of interactions between viral and host proteins is likely to continue to yield new information about important host defenses that may facilitate the development of improved treatments for a variety of human diseases.




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