scholarly journals Coelacanth SERINC2 inhibits HIV-1 infectivity and is counteracted by envelope glycoprotein from foamy virus

2021 ◽  
Author(s):  
Pavitra Ramdas ◽  
Vipin Bhardwaj ◽  
Aman Singh ◽  
Nagarjun Vijay ◽  
Ajit Chande
Keyword(s):  
Foamy Virus ◽  
Virus Envelope ◽  
Origin And Evolution ◽  
Evolutionary Origins ◽  
Evolutionarily Conserved ◽  
Foamy Viruses ◽  
Future Drug ◽  
Steady State Levels ◽  
Infection Inhibition ◽  
Hiv 1

SERINC5 restricts nef-defective HIV-1 by affecting early steps of the virus life cycle. Distant retroviruses with a wide host-range encode virulent factors in response to the challenge by SERINC5. Yet, the evolutionary origins of this anti-retroviral activity, its prevalence among the paralogs, and its ability to target retroviruses remain understudied. In agreement with previous studies, we find that four human SERINC paralogs inhibit nef-defective HIV-1, with SERINC2 being an exception. Here, we demonstrate that this lack of activity in human SERINC2 is associated with its post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD orthologs from yeast, fly, and a post-WGD-proximate SERINC2 from coelacanth to inhibit the virus. Intriguingly, Nef is unable to counter coelacanth SERINC2, indicating that such activity was directed towards other retroviruses found in coelacanth (like foamy viruses). However, foamy-derived vectors are intrinsically resistant to the action of SERINC2, and we show that the foamy virus envelope confers this resistance by affecting its steady-state levels. Our study highlights an ancient origin of anti-retroviral activity in SERINCs and a hitherto unknown interaction with a foamy virus. Importance SERINC5 constitutes a critical barrier to the propagation of retroviruses as highlighted by parallel emergence of anti-SERINC5 activities among distant retroviral lineages. Therefore, understanding the origin and evolution of these host factors will provide key information about virus-host relationships that can be exploited for future drug development. Here we show that SERINC5-mediated nef-defective HIV-1 infection inhibition is evolutionarily conserved. SERINC2 from coelacanth restricts HIV-1 and it was functionally adapted to target foamy viruses. Our findings provide insights into the evolutionary origin of anti-retroviral activity in SERINC gene family and uncover the role of SERINCs in shaping the long-term conflicts between retroviruses and their hosts.

scholarly journals Coevolution of retroviruses with SERINCs following whole-genome duplication divergence

2020 ◽  
Author(s):  
Pavitra Ramdas ◽  
Vipin Bhardwaj ◽  
Aman Singh ◽  
Nagarjun Vijay ◽  
Ajit Chande
Keyword(s):  
Gene Family ◽  
Whole Genome Duplication ◽  
Genome Duplication ◽  
Foamy Virus ◽  
Arms Race ◽  
Whole Genome ◽  
Virus Envelope ◽  
Foamy Viruses ◽  
Hiv 1

AbstractThe SERINC gene family comprises of five paralogs in humans of which SERINC3 and SERINC5 inhibit HIV-1 infectivity and are counteracted by Nef. The origin of this anti-retroviral activity, its prevalence among the remaining paralogs, and its ability to target retroviruses remain largely unknown. Here we show that despite their early divergence, the anti-retroviral activity is functionally conserved among four human SERINC paralogs with SERINC2 being an exception. The lack of activity in human SERINC2 is associated with its post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD orthologs from yeast, fly, and a post-WGD-proximate SERINC2 from coelacanth to inhibit nef-defective HIV-1. Intriguingly, potent retroviral factors from HIV-1 and MLV are not able to relieve the SERINC2-mediated particle infectivity inhibition, indicating that such activity was directed towards other retroviruses that are found in coelacanth (like foamy viruses). However, foamy-derived vectors are intrinsically resistant to the action of SERINC2, and we show that a foamy virus envelope confers this resistance. Despite the presence of weak arms-race signatures, the functional reciprocal adaptation among SERINC2 and SERINC5 and, in response, the emergence of antagonizing ability in foamy virus appears to have resulted from a long-term conflict with the host.

scholarly journals Crystal structure of prototype foamy virus (PFV) protease-reverse transcriptase fusion (PR-RT) reveals conformational plasticity: implications for function

2020 ◽  
Author(s):  
Jerry Joe E. K. Harrison ◽  
Steve Tuske ◽  
Kalyan Das ◽  
Francesc X. Ruiz ◽  
Joseph D. Bauman ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Reverse Transcriptase ◽  
Foamy Virus ◽  
Rnase H ◽  
Proteolytic Processing ◽  
Nucleic Acid Binding ◽  
Foamy Viruses ◽  
Conformational Plasticity ◽  
Polyprotein Precursor ◽  
Hiv 1

AbstractProteolytic processing of the retroviral Pol polyprotein precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN), except in foamy viruses (FVs) where only the IN domain is released. Here, we report the 2.9 Å resolution crystal structure of the mature PR-RT from prototype FV (PFV) needed for processing and reverse transcription. The monomeric PFV PR exhibits similar architecture as the HIV-1 PR but the N- and C-terminal residues are unstructured. A C-terminal extension of the PR folds into two helices that supports the RT palm subdomain and anchors the PR next to the RT. The subdomains of RT: fingers, palm, thumb, and connection, and the RNase H domain, are connected by flexible linkers and spatially arranged similarly to those in the HIV-1 RT p51 subunit. Significant spatial and conformational domain rearrangements are required for nucleic acid binding. This offers structural insight into retroviral RT conformational maturation and architecture of immature enzymes.

scholarly journals Cell-cycle dependence of foamy virus vectors

2004 ◽  
Vol 85 (10) ◽  
pp. 2925-2930 ◽  
Author(s):  
Gillian S. Patton ◽  
Otto Erlwein ◽  
Myra O. McClure
Keyword(s):  
Leukemia Virus ◽  
Foamy Virus ◽  
Human Cd34 ◽  
Immunodeficiency Virus ◽  
Foamy Viruses ◽  
Cell Cycle Dependence ◽  
Cycle Dependence ◽  
Prototypic Foamy Virus ◽  
Hiv 1

Retroviruses differ in the extent to which they are dependent on host-cell proliferation for their replication, an aspect of their replication that impacts on their vector potential. Foamy viruses offer distinct advantages over other retroviruses for development as vectors for gene therapy. A vector derived from the prototypic foamy virus (PFV), formerly known as human foamy virus (HFV), transduced aphidicolin-arrested cells five- to tenfold more efficiently than one derived from murine leukemia virus (MLV), but several-fold less efficiently than a human immunodeficiency virus type 1 (HIV-1) vector. The same relative efficiency was found following transduction of cells that had been arrested by γ-irradiation or with mitomycin C. Cells that were exposed to vector during aphidicolin arrest and were subsequently allowed to cycle were transduced significantly better by PFV than by MLV. Quiescent human CD34+ progenitor cells were transduced as efficiently by PFV as by HIV vectors (40–50 %) when transduction was assayed after the cells were allowed to cycle.

scholarly journals Analysis and Function of Prototype Foamy Virus Envelope N Glycosylation

2005 ◽  
Vol 79 (12) ◽  
pp. 7664-7672 ◽  
Author(s):  
Daniel Lüftenegger ◽  
Marcus Picard-Maureau ◽  
Nicole Stanke ◽  
Axel Rethwilm ◽  
Dirk Lindemann
Keyword(s):  
Foamy Virus ◽  
Differential Sensitivity ◽  
Leader Peptide ◽  
Temperature Sensitive ◽  
Virus Envelope ◽  
Particle Release ◽  
Prototype Foamy Virus ◽  
Glycosylation Sites ◽  
Evolutionarily Conserved ◽  
The Individual

ABSTRACT The prototype foamy virus (PFV) glycoprotein, which is essential for PFV particle release, displays a highly unusual biosynthesis, resulting in posttranslational cleavage of the precursor protein into three particle-associated subunits, i.e., leader peptide (LP), surface (SU), and transmembrane (TM). Glycosidase digestion of metabolically labeled PFV particles revealed the presence of N-linked carbohydrates on all subunits. The differential sensitivity to specific glycosidases indicated that all oligosaccharides on LP and TM are of the high-mannose or hybrid type, whereas most of those attached to SU, which contribute to about 50% of its molecular weight, are of the complex type. Individual inactivation of all 15 potential N-glycosylation sites in PFV Env demonstrated that 14 are used, i.e., 1 out of 2 in LP, 10 in SU, and 3 in TM. Analysis of the individual altered glycoproteins revealed defects in intracellular processing, support of particle release, and infectivity for three mutants, having the evolutionarily conserved glycosylation sites N8 in SU or N13 and N15 in the cysteine-rich central “sheets-and-loops” region of TM inactivated. Examination of alternative mutants with mutations affecting glycosylation or surrounding sequences at these sites indicated that inhibition of glycosylation at N8 and N13 most likely is responsible for the observed replication defects, whereas for N15 surrounding sequences seem to contribute to a temperature-sensitive phenotype. Taken together these data demonstrate that PFV Env and in particular the SU subunit are heavily N glycosylated and suggest that although most carbohydrates are dispensable individually, some evolutionarily conserved sites are important for normal Env function of FV isolates from different species.

scholarly journals Foamy Virus Envelope Glycoprotein Is Sufficient for Particle Budding and Release

2003 ◽  
Vol 77 (4) ◽  
pp. 2338-2348 ◽  
Author(s):  
Kit L. Shaw ◽  
Dirk Lindemann ◽  
Mark J. Mulligan ◽  
Paul A. Goepfert
Keyword(s):  
Leukemia Virus ◽  
Foamy Virus ◽  
Virus Envelope ◽  
Gag Proteins ◽  
Membrane Blebbing ◽  
B Virus ◽  
The Family ◽  
Foamy Viruses ◽  
Culture Supernatants ◽  
Murine Leukemia

ABSTRACT Foamy viruses (FVs) are classified in the family Retroviridae, but recent data have shown that they are not conventional retroviruses. Notably, several characteristics of their particle replication strategies are more similar to those of hepatitis B virus (HBV) than those of typical retroviruses. Compared to conventional retroviruses, which require only Gag proteins for budding and release of virus-like particles (VLPs), both FV and HBV require Env proteins. In the case of HBV, Env (S protein) alone is sufficient to form subviral particles (SVPs). Because FVs also depend on Env for budding, we tested whether FV Env alone could produce SVPs. The Env proteins of FV and murine leukemia virus (MuLV) were both released into cell culture supernatants and migrated into isopycnic gradients; however, unlike MuLV Env, FV Env displayed characteristics of SVPs. FV Env particles were of greater density than those of MuLV (1.11 versus 1.07 g/ml, respectively), which strongly suggested that the released proteins of FV Env were particulate. When we examined FV SVPs by immunoelectron microscopy, we found particles that were consistent in morphology, size, and staining with gold beads, similar to FV VLPs and unlike the particle-like structures of MuLV Env, which were more consistent with vesicles produced from nonspecific membrane “blebbing.” Taken together, our results demonstrated that FV Env alone is sufficient for particle budding. This finding is unique among retroviruses and further demonstrated the similarities between FV and HBV.

scholarly journals Crystal Structure of a Retroviral Polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT)

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1495
Author(s):  
Jerry Joe E. K. Harrison ◽  
Steve Tuske ◽  
Kalyan Das ◽  
Francesc X. Ruiz ◽  
Joseph D. Bauman ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Reverse Transcriptase ◽  
Foamy Virus ◽  
Polymerase Activity ◽  
Rnase H ◽  
Proteolytic Processing ◽  
Nucleic Acid Binding ◽  
Foamy Viruses ◽  
Polyprotein Precursor ◽  
Hiv 1

In most cases, proteolytic processing of the retroviral Pol portion of the Gag-Pol polyprotein precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN). However, foamy viruses (FVs) express Pol separately from Gag and, when Pol is processed, only the IN domain is released. Here, we report a 2.9 Å resolution crystal structure of the mature PR-RT from prototype FV (PFV) that can carry out both proteolytic processing and reverse transcription but is in a configuration not competent for proteolytic or polymerase activity. PFV PR-RT is monomeric and the architecture of PFV PR is similar to one of the subunits of HIV-1 PR, which is a dimer. There is a C-terminal extension of PFV PR (101-145) that consists of two helices which are adjacent to the base of the RT palm subdomain, and anchors PR to RT. The polymerase domain of PFV RT consists of fingers, palm, thumb, and connection subdomains whose spatial arrangements are similar to the p51 subunit of HIV-1 RT. The RNase H and polymerase domains of PFV RT are connected by flexible linkers. Significant spatial and conformational (sub)domain rearrangements are therefore required for nucleic acid binding. The structure of PFV PR-RT provides insights into the conformational maturation of retroviral Pol polyproteins.

scholarly journals An Evolutionarily Conserved Splice Generates a Secreted Env-Bet Fusion Protein during Human Foamy Virus Infection

1998 ◽  
Vol 72 (6) ◽  
pp. 4906-4910 ◽  
Author(s):  
Marie-Louise Giron ◽  
Hugues de Thé ◽  
Ali Saïb
Keyword(s):  
Chronic Infection ◽  
Foamy Virus ◽  
Human Foamy Virus ◽  
Protein Species ◽  
Reading Frame ◽  
Evolutionarily Conserved ◽  
Foamy Viruses ◽  
Fusion Glycoprotein ◽  
Infected Cells

ABSTRACT Foamy viruses (spumaretroviruses) represent a retroviral genus which exhibits unusual features relating it to pararetroviruses. Previously, we reported the existence of a protein species harboring Env, Bel, and Bet epitopes in human foamy virus (HFV)-infected cells (M. L. Giron, F. Rozain, M. C. Debons-Guillemin, M. Canivet, J. Périès, and R. Emanoil-Ravier, J. Virol. 67:3596–3600, 1993). Here, we identify this protein as a 160-kDa Env-Bet fusion glycoprotein (gp160) translated from an mRNA species harboring a highly conserved splice site which deletes the membrane anchor domain of Env and fuses the env open reading frame with that of bel1/bet. While gp160 and Bet proteins were both secreted into the supernatant, only Bet was taken up by recipient cells. Since Bet plays a key role in the switch from lytic to chronic infection, secretion of Bet and gp160, together with cellular uptake of Bet, could be highly relevant for both immune response and development of HFV infection in vivo.

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 Generation of an improved foamy virus vector by dissection of cis-acting sequences

2009 ◽  
Vol 90 (2) ◽  
pp. 481-487 ◽  
Author(s):  
Tatiana Wiktorowicz ◽  
Katrin Peters ◽  
Nicole Armbruster ◽  
Andre F. Steinert ◽  
Axel Rethwilm
Keyword(s):  
Foamy Virus ◽  
Human Mesenchymal Stem Cells ◽  
Viral Capsid ◽  
Rna Packaging ◽  
Gag Protein ◽  
Protein Precursor ◽  
Cis Acting ◽  
Foamy Viruses ◽  
Protein Incorporation ◽  
Primary Human Cells

In contrast to other retroviruses, foamy viruses (FVs) generate their Pol protein precursor independently of the Gag protein from a spliced mRNA. The exact mechanism of Pol protein incorporation into the viral capsid is poorly understood. Previously, we showed that Pol encapsidation critically depends on the packaging of (pre-) genomic RNA and identified two distinct signals within the cis-acting sequences (CASI and CASII), Pol encapsidation sequences (PESI and PESII), which are required for Pol capsid incorporation. Here, we investigated whether the presence of PESI and PESII in an FV vector is sufficient for Pol encapsidation and whether the rather extended CASII element can be shortened without loss of functionality. Our results indicate that (i) the presence of PESI and II are not sufficient for Pol encapsidation, (ii) prototype FV vectors with a shortened CASII element retain Pol incorporation and full functionality, in particular upon transducing fibroblasts and primary human mesenchymal stem cells, (iii) the presence of the central poly purine tract significantly increased the transduction rates of FV vectors and (iv) Pol encapsidation and RNA packaging can be clearly separated. In essence, we designed a new FV vector that bears approximately 850 bp less of CAS than previously established vectors and is fully functional when analysed to transduce cell lines and primary human cells.

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