Carboxy-terminal cleavage of the human foamy virus Gag precursor molecule is an essential step in the viral life cycle

Enssle, Jörg; Fischer, Nicole; Moebes, A; Mauer, Bettina; Smola, U; Rethwilm, Axel

doi:10.1128/jvi.71.10.7312-7317.1997

Cited by 72 publications

(44 citation statements)

References 36 publications

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“…Unlike Gag proteins from orthoretroviruses which are cleaved and processed into capsid, matrix and nucleoprotein, FV Gag proteins are only partially cleaved at the C-terminus generating two species: a long and a shorter proteins that only differ by 4 kDa, both being incorporated in the virion (Enssle et al, 1997). They contain three Glycine and arginine-rich regions (the GR boxes) important for the correct FV assembly and the nuclear localization of Gag (Lee and Linial, 2008;Yu et al, 1996b), the role of which is still not elucidated.…”

Section: Fv Life Cyclementioning

confidence: 99%

HTLV-3/4 and simian foamy retroviruses in humans: Discovery, epidemiology, cross-species transmission and molecular virology

et al. 2013

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Non-human primates are considered to be likely sources of viruses that can infect humans and thus pose a significant threat to human population. This is well illustrated by some retroviruses, as the simian immunodeficiency viruses and the simian T lymphotropic viruses, which have the ability to cross-species, adapt to a new host and sometimes spread. This leads to a pandemic situation for HIV-1 or an endemic one for HTLV-1. Here, we present the available data on the discovery, epidemiology, cross-species transmission and molecular virology of the recently discovered HTLV-3 and HTLV-4 deltaretroviruses, as well as the simian foamy retroviruses present in different human populations at risk, especially in central African hunters. We discuss also the natural history in humans of these retroviruses of zoonotic origin (magnitude and geographical distribution, possible inter-human transmission). In Central Africa, the increase of the bushmeat trade during the last decades has opened new possibilities for retroviral emergence in humans, especially in immuno-compromised persons.

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Section: Fv Life Cyclementioning

confidence: 99%

HTLV-3/4 and simian foamy retroviruses in humans: Discovery, epidemiology, cross-species transmission and molecular virology

et al. 2013

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“…The three GR boxes involved in distinct phases of viral replication (49,64,78) were present in all isolates. The viral protease-dependent cleavage site RAVN/TVTQ, which allows the generation of the p68 Gag subunit from the full Gag (57), which is essential for subsequent correct particle formation (19,80), displayed high homology among all isolates. Interestingly, basic residues in the Gag protein are rare and mainly represented by arginines instead of lysines, in deep contrast to orthoretroviruses, as recently reported (44).…”

Section: Isolation and Subsequent Complete Sequencing Of Sfv Strains mentioning

confidence: 99%

Genetic Characterization of Simian Foamy Viruses Infecting Humans

Rua

Betsem

Calattini

et al. 2012

J Virol

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e Simian foamy viruses (SFVs) are retroviruses that are widespread among nonhuman primates (NHPs). SFVs actively replicate in their oral cavity and can be transmitted to humans after NHP bites, giving rise to a persistent infection even decades after primary infection. Very few data on the genetic structure of such SFVs found in humans are available. In the framework of ongoing studies searching for SFV-infected humans in south Cameroon rainforest villages, we studied 38 SFV-infected hunters whose times of infection had presumably been determined. By long-term cocultures of peripheral blood mononuclear cells with BHK-21 cells, we isolated five new SFV strains and obtained complete genomes of SFV strains from chimpanzee (Pan troglodytes troglodytes; strains BAD327 and AG15), monkey (Cercopithecus nictitans; strain AG16), and gorilla (Gorilla gorilla; strains BAK74 and BAD468). These zoonotic strains share a very high degree of similarity with their NHP counterparts and have a high degree of conservation of the genetic elements important for viral replication. Interestingly, analysis of FV DNA sequences obtained before cultivation revealed variants with deletions in both the U3 region and tas that may correlate with in vivo chronicity in humans. Genomic changes in bet (a premature stop codon) and gag were also observed. To determine if such changes were specific to zoonotic strains, we studied local SFV-infected chimpanzees and found the same genomic changes. Our study reveals that natural polymorphism of SFV strains does exist at both the intersubspecies level (gag, bet) and the intrasubspecies (U3, tas) levels but does not seem to reflect a viral adaptation specific to zoonotic SFV strains. Simian foamy viruses (SFVs) are exogenous complex retroviruses of the Spumaretrovirinae subfamily (15). They are widespread in various species, including nonhuman primates (NHPs), felines, bovines, and equines, in which they cause persistent infection (46,50,60,76). Transmission of SFVs among NHPs occurs via infected body fluids, mainly through biting (6, 38), as the virus replicates in the NHP oral mucosa (22, 51, 52). Zoonotic infections have been reported in occupationally exposed individuals (4,31,63,67,72) and in more natural settings (77). Our team has developed and extended such results with studies in south Cameroon, demonstrating the presence of persistent SFV infection in a series of 52 individuals, mainly men, bitten during hunting activities in the forest by an ape (mostly gorillas) or a monkey (1, 6).Despite the wealth of data describing the ecological factors that underpin viral emergence, less is known about the evolutionary processes that allow viruses to jump species barriers, such as recombination, deletion, reassortments, and mutations (28, 32, 35, 54-56, 68, 75).Known retroviruses have emerged in humans (human T cell leukemia virus/simian T cell leukemia virus and human immunodeficiency virus/simian immunodeficiency virus) and display different levels of genetic divergence from their NHP counterparts, que...

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“…However, at least some of the Gag molecules have to be cleaved to obtain infectious virus particles. 6,40 In summary, we demonstrate an essential role for region aa 107-143 for polymerase but not protease activity, whereas the connection subdomain is important for substrate affinity, protein stability and proper function of the RT. Furthermore, our data on PR activation show that the full length PR-RT including the RNase H domain is required for PR activity.…”

Section: Discussionmentioning

confidence: 72%

“…However, analysis of the protein composition of virus particles demonstrated that in FVs Gag cleavage is only partial, whereas Pol is processed completely into PR-RT and IN. [6][7][8][9] Therefore, we wanted to determine, whether in vitro one of the two cleavage sites is preferred and cleaved Properties of Foamy Virus PR-RT with higher efficiency by wt PR-RT. Two substrates were used, containing either the natural Gag or Pol cleavage site between the proteins GB1 and GFP [ Fig.…”

Section: Protease Activitymentioning

confidence: 99%

“…In addition, FV p3 deletion mutants are able to replicate, while FVs with an inactive Gag p68=p3 cleavage site are not, demonstrating the necessity for a tight control of PR activity during FV assembly and maturation. [5][6][7][8][9] We have shown previously, that the isolated PR domain from simian FV from macaques (SFVmac) is a monomer of about 12 kDa, which has to dimerize to be active. 3,10,11 In the mature PR-RT, the PR is located Nterminally of the RT.…”

Section: Introductionmentioning

confidence: 99%

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Structural requirements for enzymatic activities of foamy virus protease‐reverse transcriptase

et al. 2013

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Reverse transcriptases (RTs) are pivotal in the life cycle of retroviruses and convert the genomic viral RNA into double-stranded DNA. The RT polymerase domain is subdivided into fingers, palm, thumb, and the connection subdomain, which links the polymerase to the C-terminal RNase H domain. In contrast to orthoretroviruses, mature RT of foamy viruses harbors the protease (PR) domain at its N-terminus (PR-RT). Therefore and due to low homology to other RTs, it is difficult to define the boundaries and functions of the (sub)domains. We introduced N- and C-terminal deletions into simian foamy virus PR-RT to investigate the impact of the truncations on the catalytic activities. Both, the RNase H domain and the connection subdomain contribute substantially to polymerase integrity and stability as well as to polymerase activity and substrate binding. The 42 amino acids long region C-terminal of the PR is important for polymerase stability and activity. PR activation via binding of PR-RT to viral RNA requires the presence of the full length PR-RT including the RNase H domain. In vitro, the cleavage efficiencies of FV PR for the Gag and Pol cleavage site are comparable, even though in virus particles only the Pol site is cleaved to completion suggesting that additional factors control PR activity and that virus maturation needs to be strictly regulated.

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Carboxy-terminal cleavage of the human foamy virus Gag precursor molecule is an essential step in the viral life cycle

Cited by 72 publications

References 36 publications

HTLV-3/4 and simian foamy retroviruses in humans: Discovery, epidemiology, cross-species transmission and molecular virology

HTLV-3/4 and simian foamy retroviruses in humans: Discovery, epidemiology, cross-species transmission and molecular virology

Genetic Characterization of Simian Foamy Viruses Infecting Humans

Structural requirements for enzymatic activities of foamy virus protease‐reverse transcriptase

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