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Review
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Prospects in Innate Immune Responses as Potential Control Strategies Against Non-Primate Lentiviruses

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Review

Prospects in Innate Immune Responses as Potential Control Strategies Against Non-Primate Lentiviruses

Lorena de Pablo-Maiso et al. Viruses.

Abstract

Lentiviruses are infectious agents of a number of animal species, including sheep, goats, horses, monkeys, cows, and cats, in addition to humans. As in the human case, the host immune response fails to control the establishment of chronic persistent infection that finally leads to a specific disease development. Despite intensive research on the development of lentivirus vaccines, it is still not clear which immune responses can protect against infection. Viral mutations resulting in escape from T-cell or antibody-mediated responses are the basis of the immune failure to control the infection. The innate immune response provides the first line of defense against viral infections in an antigen-independent manner. Antiviral innate responses are conducted by dendritic cells, macrophages, and natural killer cells, often targeted by lentiviruses, and intrinsic antiviral mechanisms exerted by all cells. Intrinsic responses depend on the recognition of the viral pathogen-associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs), and the signaling cascades leading to an antiviral state by inducing the expression of antiviral proteins, including restriction factors. This review describes the latest advances on innate immunity related to the infection by animal lentiviruses, centered on small ruminant lentiviruses (SRLV), equine infectious anemia virus (EIAV), and feline (FIV) and bovine immunodeficiency viruses (BIV), specifically focusing on the antiviral role of the major restriction factors described thus far.

Keywords: control strategies; innate immunity; non-primate lentivirus; restriction factors.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Virion particle schematic representation of animal lentiviruses. Figure depicts common structural genes and encoded proteins. Gene gag encodes the viral core proteins, including capsid (CA), matrix (MA), and nucleocapsid (NC) proteins. CA is relatively conserved, NC directly interacts with viral RNA. Gene pol encodes the replication-related enzymes, such as protease (PR), reverse transcriptase (RT) that catalyzes the viral DNA synthesis, and integrase (IN). Gene env encodes the envelope polyprotein that, after digestion by a cellular protease, result in transmembrane (TM) and surface (SU) subunits.
Figure 2
Figure 2
Proviral genomic structure of most common animal lentiviruses. Genes gag, pol, and env, as well as flanking long terminal repeats (LTRs), are common features among animal lentiviruses. Small ruminant lentiviruses (SRLV) encode three accessory genes vif, vpr-like, and rev without evidence of a transactivation activity [8]. Equine infectious anemia virus (EIAV) encodes an S2 gene whose protein may accomplish a function similar to that exerted by HIV Nef [9]. Feline immunodeficiency virus (FIV) encodes orfA with functions similar to Vpr and Nef, since it produces G2 cell cycle arrest and downregulation of E2 ubiquitin conjugating enzymes [10], respectively. Jembrana disease virus (JDV) and bovine immunodeficiency virus (BIV) encode four accessory genes, vif, tat, rev, and tmx that may exert Nef-like properties. Animal lentiviruses also encode a dUTPase subunit involved in regulating cellular dNTP ratio. BIV encodes a dUTPase-related gene without enzymatic activity.
Figure 3
Figure 3
Overview of the lentivirus replication cycle and cellular restriction factors that target lentiviruses and their viral antagonists. The key mechanisms by which restriction factors directly act upon the retroviral replication cycle, and their counteraction by viral accessory proteins, are depicted. Virus replication steps are shown with numbers. After entry, TRIM5α recognizes viral capsid and induces premature decapsidation and autoubiquitination, except in the case of Felis catus. Other measures that may inhibit the infection cycle at this stage are SAMHD1 and IFITM (interferon-induced transmembrane protein 3). Viral Vif can counteract some of these mechanisms by inducing proteasome-associated degradation. APOBEC3, which is harbored in viral particles, mediates hypermutation of the viral genome, as indicated in the inset panel. When the lentiviral genome and proteins are assembling, tetherin can trap new virions and reduce infectivity.
Figure 4
Figure 4
Animal lentiviruses innate immune sensing. Toll-like receptors (TLRs) 7, 8, and 9 can sense virus-derived nucleic acids and induce a signaling cascade involving IRAK-1 that results in the expression of inflammatory cytokines and type I-IFN, such as interferon alpha (IFN- α) and beta (IFN-β). Receptor for IFN (IFNAR) engages type I IFN molecules, inducing the expression of many antiviral proteins known as IFN-stimulated genes, among which, restriction factors are present.
Figure 5
Figure 5
Schematic representation of ovine, caprine, bovine, equine, and feline Tripartite motif-containing protein 5 alpha (TRIM5α). RING, B-box-2, coiled-coil, and PRY/SPRY domains are represented. Feline TRIM5α lacks the PRY/SPRY domain because of a premature stop codon in the mRNA transcript. Predicted structure of GenBank accession numbers: JN835300-JN835311 (ovine) and JQ582845-JQ582849 (caprine), DQ380509 (bovine), XM_014741762.2 (equine), NM_001163659 (feline).
Figure 6
Figure 6
APOBEC3 proteins encoded by primates in comparison with ovine, bovine, equine, and felines highlighting Zn2+ domains and deaminase catalytic site. Ovine, bovine, and feline encode alternative splicing derived proteins (highlighted with a discontinuous line) and a truncated isoform in the case of small ruminants.
Figure 7
Figure 7
BST2/tetherin protein structure representation including animal lentiviruses targeted species. Cytoplasmatic tail, transmembrane, coiled-coil, and GPI anchor domains are represented. The N-terminal cytoplasmatic tail of feline and equine tetherin is characterized by a shorter region compared to other species. Sheep and bovine tetherin have two and three paralogs, respectively, which inhibit virus infectivity by different mechanisms [171].

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