scholarly journals Cellular Restriction Factors: Exploiting the Body’s Antiviral Proteins to Combat HIV-1/AIDS

10.5772/19413 ◽  
2011 ◽  
Author(s):  
Jenna N. ◽  
Jessica G.K. ◽  
Clayton J. ◽  
Matthew W. ◽  
Stephen D.
Keyword(s):  
Restriction Factors ◽  
Antiviral Proteins ◽  
Hiv 1

scholarly journals APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Mollie M. McDonnell ◽  
Kate H. D. Crawford ◽  
Adam S. Dingens ◽  
Jesse D. Bloom ◽  
Michael Emerman
Keyword(s):  
Antiviral Activity ◽  
Innate Immune System ◽  
Cytidine Deaminase ◽  
Innate Immune ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Domain Protein ◽  
Antiviral Proteins ◽  
Deaminase Domain ◽  
Hiv 1

ABSTRACT Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A to A3H. These genes have either one or two cytidine deaminase domains, and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein resulted in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that use only a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity but instead inhibit formation of reverse transcription products, which correlates with their ability to form large higher-order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein Vif. IMPORTANCE As a part of the innate immune system, humans encode proteins that inhibit viruses such as HIV-1. These broadly acting antiviral proteins do not protect humans from viral infections because viruses encode proteins that antagonize the host antiviral proteins to evade the innate immune system. One such example of a host antiviral protein is APOBEC3C (A3C), which weakly inhibits HIV-1. Here, we show that we can improve the antiviral activity of A3C by duplicating the DNA sequence to create a synthetic tandem domain and, furthermore, that the proteins thus generated are relatively resistant to the viral antagonist Vif. Together, these data give insights about how nature has evolved a defense against viral pathogens such as HIV.

scholarly journals APOBEC3C tandem domain proteins create super restriction factors against HIV-1

2020 ◽  
Author(s):  
Mollie M. McDonnell ◽  
Kate H.D. Crawford ◽  
Adam S. Dingens ◽  
Jesse D. Bloom ◽  
Michael Emerman
Keyword(s):  
Antiviral Activity ◽  
Innate Immune System ◽  
Cytidine Deaminase ◽  
Innate Immune ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Domain Protein ◽  
Antiviral Proteins ◽  
Deaminase Domain ◽  
Hiv 1

AbstractHumans encode proteins, called restriction factors, that inhibit replication of viruses like HIV-1. One family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3, shortened to A3) acts by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A-A3H. These genes either have one or two cytidine deaminase domains and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein results in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that only use a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity, but instead inhibit formation of reverse transcription products which correlates with their ability to form large higher order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein, Vif.ImportanceAs a part of the innate immune system, humans encode proteins that inhibit viruses like HIV-1. These broadly acting antiviral proteins do not protect humans from viral infections because viruses encode proteins that antagonize the host antiviral proteins to evade the innate immune system. One such example of a host antiviral protein is APOBEC3C (A3C), which weakly inhibits HIV-1. Here, we show that we can improve the antiviral activity of A3C by duplicating the DNA sequence to create a synthetic tandem domain, and furthermore, are relatively resistant to the viral antagonist, Vif. Together, these data give insights about how nature has evolved a defense against viral pathogens like HIV.

Restriction Factors in HIV-1 Disease Progression

2015 ◽  
Vol 13 (6) ◽  
pp. 448-461 ◽  
Author(s):  
Natacha Merindol ◽  
Lionel Berthoux
Keyword(s):  
Disease Progression ◽  
Restriction Factors ◽  
Hiv 1

scholarly journals Foamy Viruses, Bet, and APOBEC3 Restriction

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Ananda Ayyappan Jaguva Vasudevan ◽  
Daniel Becker ◽  
Tom Luedde ◽  
Holger Gohlke ◽  
Carsten Münk
Keyword(s):  
Current Knowledge ◽  
Regulatory Protein ◽  
Host Population ◽  
Life Cycles ◽  
Restriction Factors ◽  
Host Restriction ◽  
Open Questions ◽  
Foamy Viruses ◽  
Natural Hosts ◽  
Hiv 1

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.

scholarly journals Structure, Function, and Interactions of the HIV-1 Capsid Protein

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 100
Author(s):  
Eric Rossi ◽  
Megan E. Meuser ◽  
Camille J. Cunanan ◽  
Simon Cocklin
Keyword(s):  
Life Cycle ◽  
Capsid Protein ◽  
Adaptor Proteins ◽  
Restriction Factors ◽  
Gag Polyprotein ◽  
Immunodeficiency Virus ◽  
Host Cell Factors ◽  
Hiv 1

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

scholarly journals High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

2010 ◽  
Vol 84 (23) ◽  
pp. 12300-12314 ◽  
Author(s):  
Hanna-Mari Tervo ◽  
Oliver T. Keppler
Keyword(s):  
T Cells ◽  
Late Phase ◽  
Small Animal ◽  
Receptor Complex ◽  
Restriction Factors ◽  
Cyclin T1 ◽  
Primary Rabbit ◽  
Species Specific ◽  
Hiv 1

ABSTRACT An immunocompetent, permissive, small-animal model would be valuable for the study of human immunodeficiency virus type 1 (HIV-1) pathogenesis and for the testing of drug and vaccine candidates. However, the development of such a model has been hampered by the inability of primary rodent cells to efficiently support several steps of the HIV-1 replication cycle. Although transgenesis of the HIV receptor complex and human cyclin T1 have been beneficial, additional late-phase blocks prevent robust replication of HIV-1 in rodents and limit the range of in vivo applications. In this study, we explored the HIV-1 susceptibility of rabbit primary T cells and macrophages. Envelope-specific and coreceptor-dependent entry of HIV-1 was achieved by expressing human CD4 and CCR5. A block of HIV-1 DNA synthesis, likely mediated by TRIM5, was overcome by limited changes to the HIV-1 gag gene. Unlike with mice and rats, primary cells from rabbits supported the functions of the regulatory viral proteins Tat and Rev, Gag processing, and the release of HIV-1 particles at levels comparable to those in human cells. While HIV-1 produced by rabbit T cells was highly infectious, a macrophage-specific infectivity defect became manifest by a complex pattern of mutations in the viral genome, only part of which were deamination dependent. These results demonstrate a considerable natural HIV-1 permissivity of the rabbit species and suggest that receptor complex transgenesis combined with modifications in gag and possibly vif of HIV-1 to evade species-specific restriction factors might render lagomorphs fully permissive to infection by this pathogenic human lentivirus.

scholarly journals Restriction Factors: From Intrinsic Viral Restriction to Shaping Cellular Immunity Against HIV-1

2018 ◽  
Vol 9 ◽  
Author(s):  
Marta Colomer-Lluch ◽  
Alba Ruiz ◽  
Arnaud Moris ◽  
Julia G. Prado
Keyword(s):  
Cellular Immunity ◽  
Restriction Factors ◽  
Viral Restriction ◽  
Hiv 1

Host Restriction Factors and Human Immunodeficiency Virus (HIV-1): A Dynamic Interplay Involving All Phases of the Viral Life Cycle

2018 ◽  
Vol 16 (3) ◽  
pp. 184-207 ◽  
Author(s):  
Vanessa D`Urbano ◽  
Elisa De Crignis ◽  
Maria Carla Re
Keyword(s):  
Mammalian Cells ◽  
Viral Evolution ◽  
Type I ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Immunodeficiency Virus ◽  
Lentiviral Infection ◽  
Specific Proteins ◽  
Hiv 1

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

scholarly journals Functional Mapping of Regions Involved in the Negative Imprinting of Virion Particle Infectivity and in Target Cell Protection by Interferon-Induced Transmembrane Protein 3 against HIV-1

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Romain Appourchaux ◽  
Mathilde Delpeuch ◽  
Li Zhong ◽  
Julien Burlaud-Gaillard ◽  
Kevin Tartour ◽  
...  
Keyword(s):  
Target Cell ◽  
Transmembrane Protein ◽  
Regulatory Role ◽  
Target Cells ◽  
Restriction Factors ◽  
Cell Protection ◽  
Differential Behavior ◽  
Antiviral Activities ◽  
Divergent Behavior ◽  
Hiv 1

ABSTRACT The interferon-induced transmembrane proteins (IFITMs) are a family of highly related antiviral factors that affect numerous viruses at two steps: in target cells by sequestering incoming viruses in endosomes and in producing cells by leading to the production of virions that package IFITMs and exhibit decreased infectivity. While most studies have focused on the former, little is known about the regulation of the negative imprinting of virion particle infectivity by IFITMs and about its relationship with target cell protection. Using a panel of IFITM3 mutants against HIV-1, we have explored these issues as well as others related to the biology of IFITM3, in particular virion packaging, stability, the relation to CD63/multivesicular bodies (MVBs), the modulation of cholesterol levels, and the relationship between negative imprinting of virions and target cell protection. The results that we have obtained exclude a role for cholesterol and indicate that CD63 accumulation does not directly relate to an antiviral behavior. We have defined regions that modulate the two antiviral properties of IFITM3 as well as novel domains that modulate protein stability and that, in so doing, influence the extent of its packaging into virions. The results that we have obtained, however, indicate that, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for negative imprinting. Finally, while most mutations concomitantly affect target cell protection and negative imprinting, a region in the C-terminal domain (CTD) exhibits a differential behavior, potentially highlighting the regulatory role that this domain may play in the two antiviral activities of IFITM3. IMPORTANCE IFITM proteins have been associated with the sequestration of incoming virions in endosomes (target cell protection) and with the production of virion particles that incorporate IFITMs and exhibit decreased infectivity (negative imprinting of virion infectivity). How the latter is regulated and whether these two antiviral properties are related remain unknown. By examining the behavior of a large panel of IFITM3 mutants against HIV-1, we determined that IFITM3 mutants are essentially packaged into virions proportionally to their intracellular levels of expression. However, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for the antiviral effects. Most mutations were found to concomitantly affect both antiviral properties of IFITM3, but one CTD mutant exhibited a divergent behavior, possibly highlighting a novel regulatory role for this domain. These findings thus advance our comprehension of how this class of broad antiviral restriction factors acts.

scholarly journals MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Richard J Miles ◽  
Claire Kerridge ◽  
Laura Hilditch ◽  
Christopher Monit ◽  
David A Jacques ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Cytotoxic T Lymphocyte ◽  
Cyclophilin A ◽  
Conformational Flexibility ◽  
Restriction Factors ◽  
Nuclear Entry ◽  
Linear Forms ◽  
Cofactor Binding ◽  
Cofactor Recruitment ◽  
Hiv 1

The type one interferon induced restriction factor Myxovirus resistance B (MxB) restricts HIV-1 nuclear entry evidenced by inhibition of 2-LTR but not linear forms of viral DNA. The HIV-1 capsid is the key determinant of MxB sensitivity and cofactor binding defective HIV-1 capsid mutants P90A (defective for cyclophilin A and Nup358 recruitment) and N74D (defective for CPSF6 recruitment) have reduced dependency on nuclear transport associated cofactors, altered integration targeting preferences and are not restricted by MxB expression. This has suggested that nuclear import mechanism may determine MxB sensitivity. Here we have use genetics to separate HIV-1 nuclear import cofactor dependence from MxB sensitivity. We provide evidence that MxB sensitivity depends on HIV-1 capsid conformation, rather than cofactor recruitment. We show that depleting CPSF6 to change nuclear import pathway does not impact MxB sensitivity, but mutants that recapitulate the effect of Cyclophilin A binding on capsid conformation and dynamics strongly impact MxB sensitivity. We demonstrate that HIV-1 primary isolates have different MxB sensitivities due to cytotoxic T lymphocyte (CTL) selected differences in Gag sequence but similar cofactor dependencies. Overall our work demonstrates a complex relationship between cyclophilin dependence and MxB sensitivity likely driven by CTL escape. We propose that cyclophilin binding provides conformational flexibility to HIV-1 capsid facilitating simultaneous evasion of capsid-targeting restriction factors including TRIM5 as well as MxB.

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