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Structure of TRIM5 in complex with the HIV-1 capsid lattice. (A) Average reconstruction. (B) Views of each of the six edges in the same orientation. (C) Schematic representation of the structure as a hexagon with structurally distinct edges in different colors and labeled from i to vi as shown. Legend indicates the symmetry properties of each edge, which describe the relative arrangements of SPRY and CA. (D) Tiling of a single hexagon is possible only along the iii,vi edge pair trajectory but not the i,iv or ii,v trajectories. (E) Construction of a dihexagon asymmetric unit from the hexagon unit. (F) Tessellation of the dihexagon into a planar lattice.
Source publication
TRIM5α is a restriction factor that senses incoming retrovirus cores through an unprecedented mechanism of nonself recognition. TRIM5α assembles a hexagonal lattice that avidly binds the capsid shell, which surrounds and protects the virus core. The extent to which the TRIM lattice can cover the capsid and how TRIM5α directly contacts the capsid su...
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... rod that is capped at each end by the B-box 2 domain (5, 6). The B-box 2 domain makes a trimer that links dimers into a hexagonal lattice (8,16). Although our reconstructed maps are of limited resolution, fitting the crystal structures of B-box 2/coiled-coil dimers (6) and trimers (8) resulted in an unambiguous solution (Fig. 2, B to E, and fig. S4). This is because both the B-box 2/coiled-coil trimer crystal structure (8) and our corresponding trimer reconstruction here have pronounced curvature, with the concave surface facing the capsid. In the fitted model, the N-terminal end of the B-box 2 domain is found on the cytoplasmic (convex) face of the trimer, whereas the C-terminal ...
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... with the capsid surface (Fig. 3, A and B). Guided by overlapping residues in separate crystal structures of the coiled-coil and SPRY domains (6,18,19), a computational model of the coiled-coil/SPRY substructure was generated (17). Fitting of this model positions two copies of SPRY well within the dimeric density, with only minimal adjustments ( fig. S4). Although more precise details will have to await an experimentally determined higher-resolution structure, our SPRY domain positioning satisfies multiple constraints from previous studies. Each SPRY domain is packed against the coiled coil through a short helix and an amphipathic interface previously shown to be important for capsid ...
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... of the CA tube ( fig. S6B). In the Class 2 average, two helical lines of the capsid lattice were now visible, whereas in the Class 1 average, the CA hexamers were resolved. We therefore focused on Class 1. Two additional refinement rounds produced a map in which both the TRIM hexagon and underlying CA hexamers are resolved and interpretable ( Fig. 4A and fig. S6D). In this reconstruction, the TRIM hexagon covers an area equivalent to about 11 CA hexamers. All six SPRY domain dimers in the hexagon edges and connecting densities to the CA hexamers are visible. We observed four distinct modes of SPRY/CA interactions (Fig. 4B). SPRY dimers connect two adjacent CA hexamers in edges ii, iv, and v, ...
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... TRIM hexagon and underlying CA hexamers are resolved and interpretable ( Fig. 4A and fig. S6D). In this reconstruction, the TRIM hexagon covers an area equivalent to about 11 CA hexamers. All six SPRY domain dimers in the hexagon edges and connecting densities to the CA hexamers are visible. We observed four distinct modes of SPRY/CA interactions (Fig. 4B). SPRY dimers connect two adjacent CA hexamers in edges ii, iv, and v, with edge ii having the opposite handedness as edges iv and v. ...
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... Class 1 map is globally asymmetric because the two lattices are offset translationally. This is also evident from the nonsymmetric arrangement of the six hexagon edges (Fig. 4C). Therefore, the Class 1 map cannot be the repeating unit of a TRIM5/CA superlattice (Fig. 4D). We therefore asked whether the Class 1 map represents a smaller portion of a larger asymmetric unit that can be tessellated (or tiled) into a superlattice. Because the TRIM hexagons must share edges, such a unit would require SPRY/CA ...
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... Class 1 map is globally asymmetric because the two lattices are offset translationally. This is also evident from the nonsymmetric arrangement of the six hexagon edges (Fig. 4C). Therefore, the Class 1 map cannot be the repeating unit of a TRIM5/CA superlattice (Fig. 4D). We therefore asked whether the Class 1 map represents a smaller portion of a larger asymmetric unit that can be tessellated (or tiled) into a superlattice. Because the TRIM hexagons must share edges, such a unit would require SPRY/CA contacts on opposite edges to be oriented in the same way or related by translational symmetry. This ...
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... the Class 1 map represents a smaller portion of a larger asymmetric unit that can be tessellated (or tiled) into a superlattice. Because the TRIM hexagons must share edges, such a unit would require SPRY/CA contacts on opposite edges to be oriented in the same way or related by translational symmetry. This is only true for the iii,vi edge pair (Fig. 4D). However, three of the edges are formally twofold rotationally symmetric (edges ii, iv, and v), and one is pseudo-twofold symmetric (edge i) (Fig. 4, B and C). Therefore, one can generate a larger asymmetric unit-a dihexagon-of a putative TRIM5/CA superlattice by rotating a second copy of the map around edge i and then overlapping ...
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... must share edges, such a unit would require SPRY/CA contacts on opposite edges to be oriented in the same way or related by translational symmetry. This is only true for the iii,vi edge pair (Fig. 4D). However, three of the edges are formally twofold rotationally symmetric (edges ii, iv, and v), and one is pseudo-twofold symmetric (edge i) (Fig. 4, B and C). Therefore, one can generate a larger asymmetric unit-a dihexagon-of a putative TRIM5/CA superlattice by rotating a second copy of the map around edge i and then overlapping this with the equivalent edge in the first copy (Fig. 4E). This dihexagon can now be tessellated into a planar P2 lattice (Fig. 4F). The above analysis ...
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... formally twofold rotationally symmetric (edges ii, iv, and v), and one is pseudo-twofold symmetric (edge i) (Fig. 4, B and C). Therefore, one can generate a larger asymmetric unit-a dihexagon-of a putative TRIM5/CA superlattice by rotating a second copy of the map around edge i and then overlapping this with the equivalent edge in the first copy (Fig. 4E). This dihexagon can now be tessellated into a planar P2 lattice (Fig. 4F). The above analysis explains how the TRIM hexagonal lattice can undergo limited extensions beyond the initial seed by using only four distinct types of SPRY/CA contacts. But how can TRIM5 cover the entire capsid lattice? Closer examination of the Class 2 ...
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... pseudo-twofold symmetric (edge i) (Fig. 4, B and C). Therefore, one can generate a larger asymmetric unit-a dihexagon-of a putative TRIM5/CA superlattice by rotating a second copy of the map around edge i and then overlapping this with the equivalent edge in the first copy (Fig. 4E). This dihexagon can now be tessellated into a planar P2 lattice (Fig. 4F). The above analysis explains how the TRIM hexagonal lattice can undergo limited extensions beyond the initial seed by using only four distinct types of SPRY/CA contacts. But how can TRIM5 cover the entire capsid lattice? Closer examination of the Class 2 particles indicated that these can be further classified into two additional ...
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... with Chimera (59), and the correlation between the two maps was calculated with the dfsc subroutine in Dynamo ( fig. S6D, green curve) (57). The obtained 0.143 cutoff value was 23.8 Å. We also aligned each of the six hexagon edges with the TRIM dimer reconstruction as reference, which gave an average value of 31.7 ± 1.8 Å at the 0.143 cutoff ( fig. S4B, blue ...
Citations
... TRIM5α's function is to intercept incoming viral cores during cytoplasmic transport and disrupt reverse transcription [26]. The HIV-1 CA lattice serves as a template for complementary hexagonal arrays of TRIM5α that are believed to cage and disrupt mature cores [14,23,[39][40][41][42]. Pathogenmediated templating of TRIM5α activates its function as a PRR and immune sensor, helping to establish an antiviral state [40,[43][44][45]. ...
... Although the SPRY domain is absolutely required for substrate recognition, organized assembly mediated via the B-box and coiled-coil domains is critical in overcoming weak affinity for CA [22,66]. The coiled-coil domain exhibits an extended antiparallel dimer flanked by both the B-box and RING domains, which dimerizes in the low-order state and, cooperatively with B-box, multimerizes to stabilize a trimeric interface that allows the assembly of the hexagonal lattice around capsids [42,67,68]. The coiled-coil domain with L2 limits the flexibility of the SPRY loops, allowing more precise spacing to align with template epitopes, explaining the wide restriction potential for retroviruses that share common CA symmetry [69]. ...
The evolutionary pressures exerted by viral infections have led to the development of various cellular proteins with potent antiviral activities, some of which are known as antiviral restriction factors. TRIpartite Motif-containing protein 5 alpha (TRIM5α) is a well-studied restriction factor of retroviruses that exhibits virus- and host-species-specific functions in protecting against cross-primate transmission of specific lentiviruses. This specificity is achieved at the level of the host gene through positive selection predominantly within its C-terminal B30.2/PRYSPRY domain, which is responsible for the highly specific recognition of retroviral capsids. However, more recent work has challenged this paradigm, demonstrating TRIM5α as a restriction factor for retroelements as well as phylogenetically distinct viral families, acting similarly through the recognition of viral gene products via B30.2/PRYSPRY. This spectrum of antiviral activity raises questions regarding the genetic and structural plasticity of this protein as a mediator of the recognition of a potentially diverse array of viral molecular patterns. This review highlights the dynamic evolutionary footprint of the B30.2/PRYSPRY domain in response to retroviruses while exploring the guided ‘specificity’ conferred by the totality of TRIM5α’s additional domains that may account for its recently identified promiscuity.
... Multiple other host interactors of the HIV-1 capsid have been identified such as Cyclophilin A (CypA), nucleoporins (NUPs), CPSF6, MxB and Trim5α [70]. Trim5α, studied using a TRIM5α-TRIM21 chimera construct (TRIM5-21R), has long been shown to form hexagonal lattices on the surface of HIV-1 capsids, but STA of HIV-1 CA tubes in the presence of TRIM5α has since revealed the nature of this lattice [71][72][73]. TRIM5α has also previously been observed to disrupt the HIV-1 capsid at the inter-hexamer interfaces [74]. Additionally, binding of CypA (a host dependency factor) to native HIV-1 cores has been investigated via a novel approach for probing virus-host factor interactions within purified enveloped viruses by cryo-ET, adding to key studies using helical processing [66,68,75]. ...
Developments in cryo-electron microscopy (cryo-EM) have been interwoven with the study of viruses ever since its first applications to biological systems. Following the success of single particle cryo-EM in the last decade, cryo-electron tomography (cryo-ET) is now rapidly maturing as a technology and catalysing great advancement in structural virology as its application broadens. In this review, we provide an overview of the use of cryo-ET to study viral infection biology, discussing the key workflows and strategies used in the field. We highlight the vast body of studies performed on purified viruses and virus-like particles (VLPs), as well as discussing how cryo-ET can characterise host-virus interactions and membrane fusion events. We further discuss the importance of in situ cellular imaging in revealing previously unattainable details of infection and highlight the need for validation of high-resolution findings from purified ex situ systems. We give perspectives for future developments to achieve the full potential of cryo-ET to characterise the molecular processes of viral infection.
... The tripartite motif (TRIM) family comprises several interferon-induced proteins that carry out key roles in restricting viral infections [99]. TRIM5α targets HIV-1 replication at an early stage through binding to the viral capsid and triggering ubiquitin-dependent degradation, leading to impairment of virus uncoating [100,101]. HIV-1 is unable to counteract the antiviral function of TRIM5α, making it a suitable target for the development of HIV-1 therapeutics. However, the uncoating of the HTLV-1 capsid is poorly investigated and lacks in-depth mechanistic understanding. ...
Human T lymphotropic virus-1 (HTLV-1) was the first identified oncoretrovirus, which infects and establishes a persistent infection in approximately 10–20 million people worldwide. Although only ~5% of infected individuals develop pathologies such as adult T-cell leukemia/lymphoma (ATLL) or a neuroinflammatory disorder termed HTLV-1-asssociated myelopathy/tropical spastic paraparesis (HAM/TSP), asymptomatic carriers are more susceptible to opportunistic infections. Furthermore, ATLL patients are severely immunosuppressed and prone to other malignancies and other infections. The HTLV-1 replication cycle provides ligands, mainly nucleic acids (RNA, RNA/DNA intermediates, ssDNA intermediates, and dsDNA), that are sensed by different pattern recognition receptors (PRRs) to trigger immune responses. However, the mechanisms of innate immune detection and immune responses to HTLV-1 infection are not well understood. In this review, we highlight the functional roles of different immune sensors in recognizing HTLV-1 infection in multiple cell types and the antiviral roles of host restriction factors in limiting persistent infection of HTLV-1. We also provide a comprehensive overview of intricate strategies employed by HTLV-1 to subvert the host innate immune response that may contribute to the development of HTLV-1-associated diseases. A more detailed understanding of HTLV-1-host pathogen interactions may inform novel strategies for HTLV-1 antivirals, vaccines, and treatments for ATLL or HAM/TSP.
... A 'two-plus-one' model has been demonstrated, in which a RING dimer ubiquitinates the N-terminus of a neighboring RING monomer 20 . For TRIM5, this is supported by in vitro ubiquitination rescue experiments using catalytically dead mutants 20 and structural data demonstrating a trimeric RING arrangement in assembled TRIM5 lattices 18,19,40 . For TRIM21, RING dimerization was shown to be insufficient for effective substrate-induced ubiquitination, with full activity requiring the recruitment of two RING dimers 39 . ...
TRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn’t prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates.
... Free TRIM5α in solution forms rod-shaped dimers held together by the long anti-parallel coiled-coil segment, the structural feature likely shared by most members of the TRIM family 20,21 . The coiled-coil rods are thought to function as molecular rulers of sorts that determine the preference of TRIM5α for particular spacing between distinct binding epitopes 22 . The N-terminal domains, RING and B-box, of each monomer reside almost 20 nm apart in the dimer on the opposite ends of the antiparallel coiled-coil. ...
... The reversible selfassociation of the mobile RING segments into a four-helix bundle of the RING dimer described here is likely to provide an additional contribution to the capsid binding avidity and the cooperativity of the TRIM5α assembly/disassembly process. As a result, proximity of three RING domains depends on binding of at least three TRIM5α dimers to a particular spatial arrangement of three distinct and distant sets of epitopes recognized by the SPRY domains 22 . Furthermore, because the capsid-templated TRIM5α assembly/disassembly process is highly cooperative, formation of a larger honeycomb segment may be required to ensure that RING trimers persist long enough to complete synthesis of multiple polyubiquitin chains at the vertices of the honeycomb. ...
... The honeycomb-like TRIM5α assembly on the surface of the retroviral capsid is required for the antiviral activity of the protein (see a recent comprehensive review for detailed bibliography 10 ). The architecture of the TRIM5α assembly suggests that the cooperativity between SPRY:capsid interactions and B-box:B-box interactions forms the basis of the pattern recognition functionality and promotes capsid binding22 . B-box trimerization at the vertices of the TRIM5α honeycomb brings three N-terminal RING domains into proximity. ...
TRIM5α is an E3 ubiquitin ligase of the TRIM family that binds to the capsids of primate immunodeficiency viruses and blocks viral replication after cell entry. Here we investigate how synthesis of K63-linked polyubiquitin is upregulated by transient proximity of three RING domains in honeycomb-like assemblies formed by TRIM5α on the surface of the retroviral capsid. Proximity of three RINGs creates an asymmetric arrangement, in which two RINGs form a catalytic dimer that activates E2-ubiquitin conjugates and the disordered N-terminus of the third RING acts as the substrate for N-terminal autoubiquitylation. RING dimerization is required for activation of the E2s that contribute to the antiviral function of TRIM5α, UBE2W and heterodimeric UBE2N/V2, whereas the proximity of the third RING enhances the rate of each of the two distinct steps in the autoubiquitylation process: the initial N-terminal monoubiquitylation (priming) of TRIM5α by UBE2W and the subsequent extension of the K63-linked polyubiquitin chain by UBE2N/V2. The mechanism we describe explains how recognition of infection-associated epitope patterns by TRIM proteins initiates polyubiquitin-mediated downstream events in innate immunity.
... HIV-1(M) has been reported to be insensitive to human TRIM5 because cyclophilin A (CypA) shields incoming HIV-1(M) cores 23,24 . However, simian TRIM5 variants can form a restrictive hexameric cage around HIV-1(M) cores, which inhibits viral uncoating and nuclear entry [25][26][27] . Coordination of TRIM5 trimers at cage vertices facilitates TRIM5-mediated K63 linked ubiquitin (Ub) chain synthesis and activation of AP-1 and NF-kB transcription factors 22,28,29 . ...
Of the 13 known independent zoonoses of simian immunodeficiency viruses to humans, only one, leading to human immunodeficiency virus (HIV) type 1(M) has become pandemic, causing over 80 million human infections. To understand the specific features associated with pandemic human-to-human HIV spread, we compared replication of HIV-1(M) with non-pandemic HIV-(O) and HIV-2 strains in myeloid cell models. We found that non-pandemic HIV lineages replicate less well than HIV-1(M) owing to activation of cGAS and TRIM5-mediated antiviral responses. We applied phylogenetic and X-ray crystallography structural analyses to identify differences between pandemic and non-pandemic HIV capsids. We found that genetic reversal of two specific amino acid adaptations in HIV-1(M) enables activation of TRIM5, cGAS and innate immune responses. We propose a model in which the parental lineage of pandemic HIV-1(M) evolved a capsid that prevents cGAS and TRIM5 triggering, thereby allowing silent replication in myeloid cells. We hypothesize that this capsid adaptation promotes human-to-human spread through avoidance of innate immune response activation. Innate immune evasion is key to evolution of the pandemic lineage of HIV.
... These amino acid positions localised to the N-terminal domain of HIV-2 p26 ( Figure 4) (Price et al. 2009). In addition, position 6 and 12 are located at the p26 hexamer interface surface, while 119 is next to the CyPA binding loop (Price et al. 2009;Skorupka et al. 2019;Yu et al. 2020: 5). Many of the substitutions were stable in follow-up and there was little evidence of specific substitutions being consistently selected for -agreeing with the Renaissance counting results (Figure 3). ...
Background
HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS.
Methods
Twelve treatment-naïve, HIV-2 positive participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data were included in the analysis. CD4% change over time was analysed to stratify participants into relative faster and slower progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status.
Results
In total, 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 (IQR: 28–37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors – synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface.
Conclusions
p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.
... The tripartite motif (TRIM) family contains many interferon-induced proteins involved in restriction of several viruses, including lentiviruses [60]. Among them, TRIM5α targets [61] and forming a cage around the capsid that impairs later uncoating [62] and/or directs capsids for degradation after their ubiquitination [63]. No HIV proteins have been described to directly counteract the action of TRIM5α, and resistance to this restriction factor relies on capsid mutation at the cost of viral fitness [64]. ...
Human T cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T cell leukemia/lymphoma (ATLL) and of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), was identified a few years before Human Immunodeficiency Virus (HIV). However, forty years later, our comprehension of HTLV-1 immune detection and the host immune responses to HTLV-1 is far more limited than for HIV. In addition to innate and adaptive immune responses that rely on specialized cells of the immune system, host cells may also express a range of antiviral factors that inhibit viral replication at different stages of the cycle, in a cell-autonomous manner. Multiple antiviral factors allowing such an intrinsic immunity have been primarily and extensively described in the context HIV infection. Here, we provide an overview of whether known HIV restriction factors might act on HTLV-1 replication. Interestingly, many of them do not exert any antiviral activity against HTLV-1, and we discuss viral replication cycle specificities that could account for these differences. Finally, we highlight future research directions that could help to identify antiviral factors specific to HTLV-1.
... These amino acid positions localised to the N-terminal domain of HIV-2 p26(Figure 4)(52). In addition, position 6 and 12 are located at the p26 hexamer interface surface, while 119 is next to the CyPA binding loop(52)(53)(54). Many of the variants were stable in follow-up and there was little evidence of specific variants being consistently selected for -agreeing with the Renaissance counting results(Figure 3). ...
Background: HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression.
Methods: Twelve treatment-naive, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures.
Results: In total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28-37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (rho = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5 alpha/p26 hexamer interface surface.
Conclusions: Faster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target.
... TRIM5α is one of the best-characterized TRIMs that present a restriction function against HIV-1 and other retroviruses [31,32]. Several mechanisms have been proposed for TRIM5α antiviral function. ...
Background:
Host restriction factors are cellular proteins that inhibit specific steps of the viral life cycle. Since the 1970s, several new factors have been identified, including human immunodeficiency virus-1 (HIV-1) replication restriction. Evidence accumulated in the last decade has substantially broadened our understanding of the molecular mechanisms utilized to abrogate the HIV-1 life cycle.
Summary:
In this review, we focus on the interaction between host restriction factors participating in the early phase of HIV-1 infection, particularly CA-targeting proteins. Host factors involved in the late phase of the replication cycle, such as viral assembly and egress factors, are also described. Additionally, current reports on well-known antiviral intrinsic factors, as well as other viral restriction factors with their emerging roles, are included.
Conclusion:
A comprehensive understanding of the interactions between viruses and hosts is expected to provide insight into the design of novel HIV-1 therapeutic interventions.
