Understanding Restriction Factors and Intrinsic Immunity: Insights and Lessons from the Primate Lentiviruses

Kirmaier, Andrea; Krupp, Annabel; Johnson, Welkin E.

doi:10.2217/fvl.14.25

Cited by 6 publications

(5 citation statements)

References 132 publications

(146 reference statements)

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“…HIV-1 replicates in chimpanzees, but disease and pathology require 10 years or more, and use of this model for AIDS research was discontinued decades ago. Host restriction factors prevent productive infection by HIV-1 in Macaca species (40). Simian immunodeficiency virus (SIV) is endogenous in African macaques but highly pathogenic in Asian macaques.…”

Section: Animal Models For Hiv-1 Transmissionmentioning

confidence: 99%

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Use of broadly neutralizing antibodies for HIV‐1 prevention

Pegu¹,

Hessell

Mascola³

et al. 2017

Immunological Reviews

141

152

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Summary Antibodies have a long history in antiviral therapy, but until recently they have not been actively pursued for HIV-1 due to modest potency and breadth of early human monoclonal antibodies (MAbs) and perceived insurmountable technical, financial, and logistical hurdles. Recent advances in the identification and characterization of MAbs with the ability to potently neutralize diverse HIV-1 isolates has reinvigorated discussion and testing of these products in humans, since new broadly neutralizing MAbs (bnMAbs) are more likely to be effective against worldwide strains of HIV-1. In animal models, there is abundant evidence that bnMAbs can block infection in a dose dependent manner, and the more potent bnMAbs will allow clinical testing at infusion doses that are practically achievable. Moreover, recent advances in antibody engineering are providing further improvements in MAb potency, breadth and half-life. This review summarizes the current state of the field of bnMAb protection in animal models as well as a review of variables that are critical for antiviral activity. Several bnMAbs are currently in clinical testing, and we offer perspectives on their use as pre-exposure prophylaxis (PrEP), potential benefits beyond sterilizing immunity, and a discussion of future approaches to engineer novel molecules.

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Section: Animal Models For Hiv-1 Transmissionmentioning

confidence: 99%

“…Host restriction factors prevent productive infection by HIV-1 in Macaca species. 40 Simian immunodeficiency virus (SIV) is endogenous in African macaques but highly pathogenic in Asian macaques.…”

Section: Hiv-1 and Siv Modelsmentioning

confidence: 99%

Use of broadly neutralizing antibodies for HIV‐1 prevention

Pegu¹,

Hessell

Mascola³

et al. 2017

Immunological Reviews

141

152

View full text Add to dashboard Cite

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“…CMVs are known for their distinct species-specificity resulting from long-term co-evolution with their mammalian hosts [36][37][38]. Restriction factors can act as important drivers of viral adaptation since they serve as barriers for cross-species transmission necessitating the rapid evolution of viral evasive mechanisms during co-speciation [39,40]. While signatures of positive selection are mainly detected utilizing bioinformatics tools for multiple sequence alignments, protein 3D structures have only recently been integrated into the analysis of adaptive evolution [41].…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

Schweininger

Scherer²,

Rothemund³

et al. 2021

PLoS Pathog

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Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the success of lytic replication, the herpesvirus human cytomegalovirus (HCMV) expresses the immediate-early protein IE1, which acts as an antagonist of antiviral, subnuclear structures termed PML nuclear bodies (PML-NBs). IE1 interacts directly with PML, the key protein of PML-NBs, through its core domain and disrupts the dot-like multiprotein complexes thereby abrogating the antiviral effects. Here we present the crystal structures of the human and rat cytomegalovirus core domain (IE1CORE). We found that IE1CORE domains, also including the previously characterized IE1CORE of rhesus CMV, form a distinct class of proteins that are characterized by a highly similar and unique tertiary fold and quaternary assembly. This contrasts to a marked amino acid sequence diversity suggesting that strong positive selection evolved a conserved fold, while immune selection pressure may have fostered sequence divergence of IE1. At the same time, we detected specific differences in the helix arrangements of primate versus rodent IE1CORE structures. Functional characterization revealed a conserved mechanism of PML-NB disruption, however, primate and rodent IE1 proteins were only effective in cells of the natural host species but not during cross-species infection. Remarkably, we observed that expression of HCMV IE1 allows rat cytomegalovirus replication in human cells. We conclude that cytomegaloviruses have evolved a distinct protein tertiary structure of IE1 to effectively bind and inactivate an important cellular restriction factor. Furthermore, our data show that the IE1 fold has been adapted to maximize the efficacy of PML targeting in a species-specific manner and support the concept that the PML-NBs-based intrinsic defense constitutes a barrier to cross-species transmission of HCMV.

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“…Studies of cross-species transmissions of African SIV strains to Asian macaques have also revealed how the SIV capsid adapts to the selection pressure imposed by TRIM5 proteins [ 276 ]. A well-used model is RM infection with primary or minimally passaged SIV strains from sooty mangabeys (SIVsmm), which are sensitive to restriction by RM TRIM5α and TRIMCyp.…”

Section: Capsid-targeting Antiviral Moleculesmentioning

confidence: 99%

HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules

Saito

Yamashita

2021

Retrovirology

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The HIV-1 capsid, a conical shell encasing viral nucleoprotein complexes, is involved in multiple post-entry processes during viral replication. Many host factors can directly bind to the HIV-1 capsid protein (CA) and either promote or prevent HIV-1 infection. The viral capsid is currently being explored as a novel target for therapeutic interventions. In the past few decades, significant progress has been made in our understanding of the capsid–host interactions and mechanisms of action of capsid-targeting antivirals. At the same time, a large number of different viral capsids, which derive from many HIV-1 mutants, naturally occurring variants, or diverse lentiviruses, have been characterized for their interactions with capsid-binding molecules in great detail utilizing various experimental techniques. This review provides an overview of how sequence variation in CA influences phenotypic properties of HIV-1. We will focus on sequence differences that alter capsid–host interactions and give a brief account of drug resistant mutations in CA and their mutational effects on viral phenotypes. Increased knowledge of the sequence-function relationship of CA helps us deepen our understanding of the adaptive potential of the viral capsid.

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Understanding Restriction Factors and Intrinsic Immunity: Insights and Lessons from the Primate Lentiviruses

Cited by 6 publications

References 132 publications

Use of broadly neutralizing antibodies for HIV‐1 prevention

Use of broadly neutralizing antibodies for HIV‐1 prevention

Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules

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