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Cornelis W. A. Pleij - One of the best experts on this subject based on the ideXlab platform.
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stem loop structures can effectively substitute for an rna pseudoknot in 1 ribosomal frameshifting
Nucleic Acids Research, 2011Co-Authors: Mathieu H M Noteborn, Cornelis W. A. Pleij, René C. L. OlsthoornAbstract:−1 Programmed ribosomal frameshifting (PRF) in synthesizing the gag-pro precursor polyprotein of Simian Retrovirus type-1 (SRV-1) is stimulated by a classical H-type pseudoknot which forms an extended triple helix involving base–base and base–sugar interactions between loop and stem nucleotides. Recently, we showed that mutation of bases involved in triple helix formation affected frameshifting, again emphasizing the role of the triple helix in −1 PRF. Here, we investigated the efficiency of hairpins of similar base pair composition as the SRV-1 gag-pro pseudoknot. Although not capable of triple helix formation they proved worthy stimulators of frameshifting. Subsequent investigation of ~30 different hairpin constructs revealed that next to thermodynamic stability, loop size and composition and stem irregularities can influence frameshifting. Interestingly, hairpins carrying the stable GAAA tetraloop were significantly less shifty than other hairpins, including those with a UUCG motif. The data are discussed in relation to natural shifty hairpins.
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Functional analysis of the SRV-1 RNA frameshifting pseudoknot
Nucleic Acids Research, 2010Co-Authors: René C. L. Olsthoorn, Richard Reumerman, Cornelis W. A. Pleij, Cornelis W. Hilbers, Hans A. HeusAbstract:Simian Retrovirus type-1 uses programmed ribosomal frameshifting to control expression of the Gag-Pol polyprotein from overlapping gag and pol open-reading frames. The frameshifting signal consists of a heptanucleotide slippery sequence and a downstream-located 12-base pair pseudoknot. The solution structure of this pseudoknot, previously solved by NMR [Michiels,P.J., Versleijen,A.A., Verlaan,P.W., Pleij,C.W., Hilbers,C.W. and Heus,H.A. (2001) Solution structure of the pseudoknot of SRV-1 RNA, involved in ribosomal frameshifting. J. Mol. Biol., 310, 1109–1123] has a classical H-type fold and forms an extended triple helix by interactions between loop 2 and the minor groove of stem 1 involving base–base and base–sugar contacts. A mutational analysis was performed to test the functional importance of the triple helix for � 1 frameshifting in vitro. Changing bases in L2 or base pairs in S1 involved in a base triple resulted in a 2- to 5-fold decrease in frameshifting efficiency. Alterations in the length of L2 had adverse effects on frameshifting. The in vitro effects were well reproduced in vivo, although the effect of enlarging L2 was more dramatic in vivo. The putative role of refolding kinetics of frameshifter pseudoknots is discussed. Overall, the data emphasize the role of the triple helix in � 1 frameshifting.
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Functional analysis of the SRV-1 RNA frameshifting pseudoknot. Nucleic Acids Res., doi:10.1093/nar/ gkq629. [Epub ahead of print
2010Co-Authors: René C. L. Olsthoorn, Richard Reumerman, Cornelis W. A. Pleij, Cornelis W. Hilbers, Hans A. HeusAbstract:Simian Retrovirus type-1 uses programmed riboso-mal frameshifting to control expression of the Gag-Pol polyprotein from overlapping gag and pol open-reading frames. The frameshifting signal consists of a heptanucleotide slippery sequence and a downstream-located 12-base pair pseudoknot. The solution structure of this pseudoknot, previously solved by NMR [Michiels,P.J., Versleijen,A.A., Verlaan,P.W., Pleij,C.W., Hilbers,C.W. and Heus,H.A. (2001) Solution structure of the pseudoknot of SRV-1 RNA, involved in ribosomal frameshifting. J. Mol. Biol., 310, 1109–1123] has a classical H-type fold and forms an extended triple helix by interactions between loop 2 and the minor groove of stem 1 involving base–base and base–sugar contacts. A mu-tational analysis was performed to test the functional importance of the triple helix for 1 frameshifting in vitro. Changing bases in L2 or base pairs in S1 involved in a base triple resulted in a 2- to 5-fold decrease in frameshifting efficiency. Alterations in the length of L2 had adverse effects on frameshift-ing. The in vitro effects were well reproduced in vivo, although the effect of enlarging L2 was more dramatic in vivo. The putative role of refolding kinetics of frameshifter pseudoknots is discussed. Overall, the data emphasize the role of the triple helix in 1 frameshifting
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solution structure of the pseudoknot of srv 1 rna involved in ribosomal frameshifting
Journal of Molecular Biology, 2001Co-Authors: Paul J. A. Michiels, Cornelis W. A. Pleij, Cornelis W. Hilbers, Alexandra A M Versleijen, Paul W G Verlaan, Hans A. HeusAbstract:RNA pseudoknots play important roles in many biological processes. In the Simian Retrovirus type-1 (SRV-1) a pseudoknot together with a heptanucleotide slippery sequence are responsible for programmed ribosomal frameshifting, a translational recoding mechanism used to control expression of the Gag-Pol polyprotein from overlapping gag and pol open reading frames. Here we present the three-dimensional structure of the SRV-1 pseudoknot determined by NMR. The structure has a classical H-type fold and forms a triple helix by interactions between loop 2 and the minor groove of stem 1 involving base-base and base-sugar interactions and a ribose zipper motif, not identified in pseudoknots so far. Further stabilization is provided by a stack of five adenine bases and a uracil in loop 2, enforcing a cytidine to bulge. The two stems of the pseudoknot stack upon each other, demonstrating that a pseudoknot without an intercalated base at the junction can induce efficient frameshifting. Results of mutagenesis data are explained in context with the present three-dimensional structure. The two base-pairs at the junction of stem 1 and 2 have a helical twist of approximately 49 degrees, allowing proper alignment and close approach of the three different strands at the junction. In addition to the overwound junction the structure is somewhat kinked between stem 1 and 2, assisting the single adenosine in spanning the major groove of stem 2. Geometrical models are presented that reveal the importance of the magnitude of the helical twist at the junction in determining the overall architecture of classical pseudoknots, in particular related to the opening of the minor groove of stem 1 and the orientation of stem 2, which determines the number of loop 1 nucleotides that span its major groove.
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analysis of the role of the pseudoknot component in the srv 1 gag pro ribosomal frameshift signal loop lengths and stability of the stem regions
RNA, 1995Co-Authors: E Ten B Dam, P W Verlaan, Cornelis W. A. PleijAbstract:The Simian Retrovirus-1 (SRV-1) gag-pro frameshift signal was identified in previous work, and the overall structure of the pseudoknot involved was confirmed (ten Dam E, Brierley I, Inglis S, Pleij C, 1994, Nucleic Acids Res 22:2304-2310). Here we report on the importance of specific elements within the pseudoknot. Some mutations in stem S1 that maintain base pairing have reduced frameshift efficiencies. This indicates that base pairing in itself is not sufficient. In contrast, frameshifting correlates qualitatively with the calculated stability of mutations in S2. The stems thus play different roles in the frameshift event. The nature of the base in L1 has little influence on frameshift efficiency. It is however required to bridge S2; deleting it lowers frameshifting from 23 to 9%. In L2, frameshift efficiency was not affected in a mutant that changed 10 to 12 bases. This makes it unlikely that the primary sequence of L2 plays a role in -1 frameshifting, in contrast to readthrough in Moloney murine leukemia virus (Wills N, Gesteland R, Atkins J, 1994, EMBO J 13:4137-4144). Deletions of 2 and 3 bases gave more frameshifting than the wild type, probably reflecting the increased stability of the pseudoknot due to a shorter loop L2. Deleting even more bases reduces frameshifting compared to wild-type levels. At this point, stress will build up in L2, and this will reduce overall pseudoknot stability.
Barbara K. Felber - One of the best experts on this subject based on the ideXlab platform.
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Effect of posttranscriptional regulatory elements on transgene expression and virus production in the context of Retrovirus vectors.
Virology, 2005Co-Authors: Juraj Hlavaty, Barbara K. Felber, Matthias Schittmayer, Anika Stracke, Gerrit Jandl, Elzbieta Knapp, Brian Salmons, Walter H. Günzburg, Matthias RennerAbstract:Abstract Ineffective transgene expression in a sufficient amount of target cells is still a limitation in retroviral vector mediated gene therapy. Thus, we systematically evaluated four genetic modulators, (i) the woodchuck posttranscriptional regulatory element (WPRE), (ii) the mouse RNA transport element (RTE), (iii) the constitutive transport element (CTE) of the Simian Retrovirus type 1 (SRV-1), and (iv) the 5′ untranslated region of the human heat shock protein 70 (Hsp70 5′UTR), all of them involved in the posttranscriptional control of mRNA nucleo/cytoplasmatic transport, RNA stability, and translation efficiency, in an MLV-based Retrovirus vector context. Insertion of the WPRE into the Retrovirus vector resulted in enhancement of transgene expression (EGFP) both in transfected virus producing cells as well as in infected recipient cells irrespective of the location in the vector. The best effect was observed with two copies of the WPRE, 3′ of the transgene and in the 3′ untranslated region of the vector backbone. However, oligomerization of this element does not further increase transgene expression. Presence of the WPRE resulted also in an increase in virus production. Introduction of the CTE and/or RTE in the retroviral vector did not alter transgene expression and infectious particle production. Positive effects were observed only in vectors harboring the CTE and/or RTE in combination with the WPRE. The activity of the Hsp70 5′UTR as a translational enhancer was found to be negligible in the context of the retroviral vector. However, interference of the Hsp70 5′UTR strong secondary structure with the packaging sequence of the viral RNA was experimentally excluded as being the cause of this. These data suggest that only the WPRE is a suitable element for the improvement of transgene expression and oncoretroviral vector production.
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mutations in the nuclear export signal of human ran binding protein ranbp1 block the rev mediated posttranscriptional regulation of human immunodeficiency virus type 1
Journal of Biological Chemistry, 1997Co-Authors: Andrei S. Zolotukhin, Barbara K. FelberAbstract:We identified a region in the human Ran GTPase-binding protein RanBP1 that shares similarities to the nuclear export signal of the inhibitor of the cAMP-dependent protein kinase. Mutational analysis confirmed that this region is responsible for the cytoplasmic accumulation of RanBP1 and can functionally replace the nuclear export signal of Rev of human immunodeficiency virus type 1. We showed that RanBP1 interferes with Rev-mediated expression of human immunodeficiency virus type 1, whereas the RanBP1 with inactivated nuclear export signal abrogates Rev function. Expression of a Rev-independent molecular clone, which is regulated via the constitutive transport element (CTE) of the Simian Retrovirus type 1, is not affected. These findings indicate that Rev and RanBP1 compete for the same nuclear export pathway, whereas Rev- and the CTE-mediated pathways are distinct. The inhibition of Rev function is independent of the ability of RanBP1 to associate with Ran and therefore, it is not likely a result of interference with Ran function. These data suggest that RanBP1 interacts with Rev at the putative nuclear receptor and, hence, shares a step in posttranscriptional pathway with Rev.
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efficient expression of the human papillomavirus type 16 l1 protein in epithelial cells by using rev and the rev responsive element of human immunodeficiency virus or the cis acting transactivation element of Simian Retrovirus type 1
Journal of Virology, 1995Co-Authors: Wei Tan, Andrei S. Zolotukhin, George N. Pavlakis, Barbara K. Felber, Stefan SchwartzAbstract:Production of the human papillomavirus (HPV) late gene products L1 and L2 is limited to terminally differentiated keratinocytes. Here, we demonstrate that mRNA encoding the HPV-16 L1 capsid protein contains cis-acting RNA elements that inhibit expression at the posttranscriptional level. While cytoplasmic L1 mRNA is detectable in transfected HeLa cells, L1 protein is not produced. We have identified at least one major inhibitory element that is located within the L1 open reading frame, whereas another negative element had been reported to lie in the 3'-untranslated region of L1. The presence of these elements may explain the lack of HPV late gene expression in undifferentiated epithelial cells. Efficient production of HPV-16 L1 could be achieved with posttranscriptional regulatory elements of human immunodeficiency virus type 1 or Simian Retrovirus type 1. L1 protein was expressed in the presence of human immunodeficiency virus type 1 Rev from hybrid mRNAs containing the RNA binding site for Rev (Rev-responsive element). In addition, we have achieved efficient expression of L1 from hybrid mRNAs containing a cis-acting transactivation element from Simian Retrovirus type 1. Our data show that HPV-16 L1 protein production is regulated posttranscriptionally. This regulated expression may allow virus production in terminally differentiated epithelial cells and is probably a conserved and important mechanism for HPV expression.
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Continuous propagation of RRE(-) and Rev(-)RRE(-) human immunodeficiency virus type 1 molecular clones containing a cis-acting element of Simian Retrovirus type 1 in human peripheral blood lymphocytes.
Journal of virology, 1994Co-Authors: Andrei S. Zolotukhin, Antonio Valentin, George N. Pavlakis, Barbara K. FelberAbstract:Abstract Molecular clones of human immunodeficiency virus type 1 that contained either 37 point mutations in the Rev-responsive element (RRE) that did not affect the overlapping env reading frame or both a mutated RRE and two mutations that eliminated Rev were constructed. The mutations in the RRE were shown to remove both negative and Rev-inducible positive effects of the RRE on gene expression (G. Nasioulas, A. S. Zolotukhin, C. Tabernero, L. Solomin, C. P. Cunningham, G. N. Pavlakis, and B. K. Felber, J. Virol. 68:2986-2993, 1994). Upon insertion of a cis-acting element of Simian Retrovirus type 1 (SRV-1) into these clones, both RRE(-) and Rev(-)RRE(-) clones were expressed efficiently. The element of SRV-1 has properties similar to those of the recently identified element of Mason-Pfizer monkey virus (M. Bray, S. Prasad, J. W. Dubay, E. Hunter, K.-T. Jeang, D. Rekosh, and M.-L. Hammarskjold, Proc. Natl. Acad. Sci. USA 4:1256-1260, 1994). We demonstrated that virus preparations produced after transfections of these SRV-1 element-containing molecular clones in human cells were infectious after cell-free transmission, that they replicated about 5 to 10 times less efficiently than wild-type virus, and that they were propagated continuously for more than 7 months in human peripheral blood mononuclear cells. Growth characteristics and sequence analysis of these viruses after long-term culture demonstrated that no RRE(+)Rev(+) revertants developed. These data demonstrate that human immunodeficiency virus type 1 Rev and RRE can be replaced by heterologous regulatory systems, resulting in efficient virus production. The resulting Rev(-)RRE(-) virus can be prepared and propagated efficiently in tissue culture and can be used for further studies of the life cycle of the virus. The data also suggest that Rev acts exclusively through the RRE interaction and that it does not have any additional essential function in the life cycle of the virus.
Andrei S. Zolotukhin - One of the best experts on this subject based on the ideXlab platform.
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mutations in the nuclear export signal of human ran binding protein ranbp1 block the rev mediated posttranscriptional regulation of human immunodeficiency virus type 1
Journal of Biological Chemistry, 1997Co-Authors: Andrei S. Zolotukhin, Barbara K. FelberAbstract:We identified a region in the human Ran GTPase-binding protein RanBP1 that shares similarities to the nuclear export signal of the inhibitor of the cAMP-dependent protein kinase. Mutational analysis confirmed that this region is responsible for the cytoplasmic accumulation of RanBP1 and can functionally replace the nuclear export signal of Rev of human immunodeficiency virus type 1. We showed that RanBP1 interferes with Rev-mediated expression of human immunodeficiency virus type 1, whereas the RanBP1 with inactivated nuclear export signal abrogates Rev function. Expression of a Rev-independent molecular clone, which is regulated via the constitutive transport element (CTE) of the Simian Retrovirus type 1, is not affected. These findings indicate that Rev and RanBP1 compete for the same nuclear export pathway, whereas Rev- and the CTE-mediated pathways are distinct. The inhibition of Rev function is independent of the ability of RanBP1 to associate with Ran and therefore, it is not likely a result of interference with Ran function. These data suggest that RanBP1 interacts with Rev at the putative nuclear receptor and, hence, shares a step in posttranscriptional pathway with Rev.
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efficient expression of the human papillomavirus type 16 l1 protein in epithelial cells by using rev and the rev responsive element of human immunodeficiency virus or the cis acting transactivation element of Simian Retrovirus type 1
Journal of Virology, 1995Co-Authors: Wei Tan, Andrei S. Zolotukhin, George N. Pavlakis, Barbara K. Felber, Stefan SchwartzAbstract:Production of the human papillomavirus (HPV) late gene products L1 and L2 is limited to terminally differentiated keratinocytes. Here, we demonstrate that mRNA encoding the HPV-16 L1 capsid protein contains cis-acting RNA elements that inhibit expression at the posttranscriptional level. While cytoplasmic L1 mRNA is detectable in transfected HeLa cells, L1 protein is not produced. We have identified at least one major inhibitory element that is located within the L1 open reading frame, whereas another negative element had been reported to lie in the 3'-untranslated region of L1. The presence of these elements may explain the lack of HPV late gene expression in undifferentiated epithelial cells. Efficient production of HPV-16 L1 could be achieved with posttranscriptional regulatory elements of human immunodeficiency virus type 1 or Simian Retrovirus type 1. L1 protein was expressed in the presence of human immunodeficiency virus type 1 Rev from hybrid mRNAs containing the RNA binding site for Rev (Rev-responsive element). In addition, we have achieved efficient expression of L1 from hybrid mRNAs containing a cis-acting transactivation element from Simian Retrovirus type 1. Our data show that HPV-16 L1 protein production is regulated posttranscriptionally. This regulated expression may allow virus production in terminally differentiated epithelial cells and is probably a conserved and important mechanism for HPV expression.
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Continuous propagation of RRE(-) and Rev(-)RRE(-) human immunodeficiency virus type 1 molecular clones containing a cis-acting element of Simian Retrovirus type 1 in human peripheral blood lymphocytes.
Journal of virology, 1994Co-Authors: Andrei S. Zolotukhin, Antonio Valentin, George N. Pavlakis, Barbara K. FelberAbstract:Abstract Molecular clones of human immunodeficiency virus type 1 that contained either 37 point mutations in the Rev-responsive element (RRE) that did not affect the overlapping env reading frame or both a mutated RRE and two mutations that eliminated Rev were constructed. The mutations in the RRE were shown to remove both negative and Rev-inducible positive effects of the RRE on gene expression (G. Nasioulas, A. S. Zolotukhin, C. Tabernero, L. Solomin, C. P. Cunningham, G. N. Pavlakis, and B. K. Felber, J. Virol. 68:2986-2993, 1994). Upon insertion of a cis-acting element of Simian Retrovirus type 1 (SRV-1) into these clones, both RRE(-) and Rev(-)RRE(-) clones were expressed efficiently. The element of SRV-1 has properties similar to those of the recently identified element of Mason-Pfizer monkey virus (M. Bray, S. Prasad, J. W. Dubay, E. Hunter, K.-T. Jeang, D. Rekosh, and M.-L. Hammarskjold, Proc. Natl. Acad. Sci. USA 4:1256-1260, 1994). We demonstrated that virus preparations produced after transfections of these SRV-1 element-containing molecular clones in human cells were infectious after cell-free transmission, that they replicated about 5 to 10 times less efficiently than wild-type virus, and that they were propagated continuously for more than 7 months in human peripheral blood mononuclear cells. Growth characteristics and sequence analysis of these viruses after long-term culture demonstrated that no RRE(+)Rev(+) revertants developed. These data demonstrate that human immunodeficiency virus type 1 Rev and RRE can be replaced by heterologous regulatory systems, resulting in efficient virus production. The resulting Rev(-)RRE(-) virus can be prepared and propagated efficiently in tissue culture and can be used for further studies of the life cycle of the virus. The data also suggest that Rev acts exclusively through the RRE interaction and that it does not have any additional essential function in the life cycle of the virus.
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Immunodeficiency Virus Type 1 Molecular Clones Containing a cis-Acting Element of Simian Retrovirus Type 1
1994Co-Authors: In Human Peripheral Blood Lymphocytes, Andrei S. Zolotukhin, Antonio Valentin, George N. Pavlakis, K. FelberAbstract:Molecular clones of human immunodeficiency virus type 1 that contained either 37 point mutations in the Rev-responsive element (RRE) that did not affect the overlapping env reading frame or both a mutated RRE and two mutations that eliminated Rev were constructed. The mutations in the RRE were shown to remove both negative and Rev-inducible positive elfects of the RRE on gene expression (G. Nasioulas, A. S. Zolotukhin, C. Tabernero, L. Solomin, C. P. Cunningham, G. N. Pavlakis, and B. K. Felber, J. Virol. 68:2986-2993, 1994). Upon insertion of a cis-acting element of Simian Retrovirus type 1 (SRV-1) into these clones, both RRE(-) and Rev(-)RRE(-) clones were expressed efficiently. The element of SRV-1 has properties similar to those of the recently identified element of Mason-Pfizer monkey virus (M. Bray, S. Prasad, J. W. Dubay, E. Hunter, K.-T
Antoine Gessain - One of the best experts on this subject based on the ideXlab platform.
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High level of inter-species transmission of Simian foamy virus from non-human primates to humans in Gabon, central Africa
Retrovirology, 2011Co-Authors: Augustin Mouinga-ondémé, Melanie Caron, Antoine Gessain, Mirdad KazanjiAbstract:Each of the pathogenic human Retroviruses (HIV-1/2 and HTLV-1) has a non-human primate (NHP) counterpart, and the presence of these Retroviruses in humans results from interspecies transmission. The passage of another Simian Retrovirus, Simian foamy virus (SFV), from NHPs to humans has been reported. Here, we evaluated the natural history of SFV in a free-ranging colony of mandrills (CIRMF primate center) and in mandrills living in natura in Gabon (central Africa). We also determined the SFV prevalence in a series of 497 NHP living in different parts of Gabon. Lastly, we investigated the possible transmission of SFVs to humans.
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two distinct variants of Simian foamy virus in naturally infected mandrills mandrillus sphinx and cross species transmission to humans
Retrovirology, 2010Co-Authors: Augustin Mouingaondeme, Bettina Salle, Edouard Betsem, Melanie Caron, Noemie Renault, Paul Telfer, Preston A. Marx, Maria Makuwa, Ali Saïb, Antoine GessainAbstract:Background: Each of the pathogenic human Retroviruses (HIV-1/2 and HTLV-1) has a nonhuman primate counterpart, and the presence of these Retroviruses in humans results from interspecies transmission. The passage of another Simian Retrovirus, Simian foamy virus (SFV), from apes or monkeys to humans has been reported. Mandrillus sphinx, a monkey species living in central Africa, is naturally infected with SFV. We evaluated the natural history of the virus in a free-ranging colony of mandrills and investigated possible transmission of mandrill SFV to humans. Results: We studied 84 semi-free-ranging captive mandrills at the Primate Centre of the Centre International de Recherches Medicales de Franceville (Gabon) and 15 wild mandrills caught in various areas of the country. The presence of SFV was also evaluated in 20 people who worked closely with mandrills and other nonhuman primates. SFV infection was determined by specific serological (Western blot) and molecular (nested PCR of the integrase region in the polymerase gene) assays. Seropositivity for SFV was found in 70/84 (83%) captive and 9/15 (60%) wild-caught mandrills and in 2/20 (10%) humans. The 425-bp SFV integrase fragment was detected in peripheral blood DNA from 53 captive and 8 wild-caught mandrills and in two personnel. Sequence and phylogenetic studies demonstrated the presence of two distinct strains of mandrill SFV, one clade including SFVs from mandrills living in the northern part of Gabon and the second consisting of SFV from animals living in the south. One man who had been bitten 10 years earlier by a mandrill and another bitten 22 years earlier by a macaque were found to be SFV infected, both at the Primate Centre. The second man had a sequence close to SFVmac sequences. Comparative sequence analysis of the virus from the first man and from the mandrill showed nearly identical sequences, indicating genetic stability of SFV over time. Conclusion: Our results show a high prevalence of SFV infection in a semi-free-ranging colony of mandrills, with the presence of two different strains. We also showed transmission of SFV from a mandrill and a macaque to humans.
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Two distinct variants of Simian foamy virus in naturally infected mandrills (Mandrillus sphinx) and cross-species transmission to humans.
Retrovirology, 2010Co-Authors: Augustin Mouinga-ondémé, Bettina Salle, Edouard Betsem, Melanie Caron, Noemie Renault, Paul Telfer, Maria Makuwa, Ali Saïb, Preston Marx, Antoine GessainAbstract:BACKGROUND: Each of the pathogenic human Retroviruses (HIV-1/2 and HTLV-1) has a nonhuman primate counterpart, and the presence of these Retroviruses in humans results from interspecies transmission. The passage of another Simian Retrovirus, Simian foamy virus (SFV), from apes or monkeys to humans has been reported. Mandrillus sphinx, a monkey species living in central Africa, is naturally infected with SFV. We evaluated the natural history of the virus in a free-ranging colony of mandrills and investigated possible transmission of mandrill SFV to humans. RESULTS: We studied 84 semi-free-ranging captive mandrills at the Primate Centre of the Centre International de Recherches Médicales de Franceville (Gabon) and 15 wild mandrills caught in various areas of the country. The presence of SFV was also evaluated in 20 people who worked closely with mandrills and other nonhuman primates. SFV infection was determined by specific serological (Western blot) and molecular (nested PCR of the integrase region in the polymerase gene) assays. Seropositivity for SFV was found in 70/84 (83%) captive and 9/15 (60%) wild-caught mandrills and in 2/20 (10%) humans. The 425-bp SFV integrase fragment was detected in peripheral blood DNA from 53 captive and 8 wild-caught mandrills and in two personnel. Sequence and phylogenetic studies demonstrated the presence of two distinct strains of mandrill SFV, one clade including SFVs from mandrills living in the northern part of Gabon and the second consisting of SFV from animals living in the south. One man who had been bitten 10 years earlier by a mandrill and another bitten 22 years earlier by a macaque were found to be SFV infected, both at the Primate Centre. The second man had a sequence close to SFVmac sequences. Comparative sequence analysis of the virus from the first man and from the mandrill showed nearly identical sequences, indicating genetic stability of SFV over time. CONCLUSION: Our results show a high prevalence of SFV infection in a semi-free-ranging colony of mandrills, with the presence of two different strains. We also showed transmission of SFV from a mandrill and a macaque to humans.
William M. Switzer - One of the best experts on this subject based on the ideXlab platform.
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Dual Simian Foamy Virus/Human Immunodeficiency Virus Type 1 Infections in Persons from Côte d’Ivoire
PLOS ONE, 2016Co-Authors: William M. Switzer, Shaohua Tang, Haoqiang Zheng, Anupama Shankar, Patrick Sprinkle, Vickie Sullivan, Timothy C. Granade, Walid HeneineAbstract:Zoonotic transmission of Simian Retroviruses in West-Central Africa occurring in primate hunters has resulted in pandemic spread of human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs). While Simian foamy virus (SFV) and Simian T- lymphotropic virus (STLV)-like infection were reported in healthy persons exposed to nonhuman primates (NHPs) in West-Central Africa, less is known about the distribution of these viruses in Western Africa and in hospitalized populations. We serologically screened for SFV and STLV infection using 1,529 specimens collected between 1985 and 1997 from Cote d'Ivoire patients with high HIV prevalence. PCR amplification and analysis of SFV, STLV, and HIV/SIV sequences from PBMCs was used to investigate possible Simian origin of infection. We confirmed SFV antibodies in three persons (0.2%), two of whom were HIV-1-infected. SFV polymerase (pol) and LTR sequences were detected in PBMC DNA available for one HIV-infected person. Phylogenetic comparisons with new SFV sequences from African guenons showed infection likely originated from a Chlorocebus sabaeus monkey endemic to Cote d'Ivoire. 4.6% of persons were HTLV seropositive and PCR testing of PBMCs from 15 HTLV seroreactive persons identified nine with HTLV-1 and one with HTLV-2 LTR sequences. Phylogenetic analysis showed that two persons had STLV-1-like infections, seven were HTLV-1, and one was an HTLV-2 infection. 310/858 (53%), 8/858 (0.93%), and 18/858 (2.1%) were HIV-1, HIV-2, and HIV-positive but undifferentiated by serology, respectively. No SIV sequences were found in persons with HIV-2 antibodies (n = 1) or with undifferentiated HIV results (n = 7). We document SFV, STLV-1-like, and dual SFV/HIV infection in Cote d'Ivoire expanding the geographic range for zoonotic Simian Retrovirus transmission to West Africa. These findings highlight the need to define the public health consequences of these infections. Studying dual HIV-1/SFV infections in immunocompromised populations may provide a new opportunity to better understand SFV pathogenicity and transmissibility in humans.
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dual Simian foamy virus human immunodeficiency virus type 1 infections in persons from cote d ivoire
PLOS ONE, 2016Co-Authors: William M. Switzer, Shaohua Tang, Haoqiang Zheng, Anupama Shankar, Patrick Sprinkle, Vickie Sullivan, Timothy C. Granade, Walid HeneineAbstract:Zoonotic transmission of Simian Retroviruses in West-Central Africa occurring in primate hunters has resulted in pandemic spread of human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs). While Simian foamy virus (SFV) and Simian T- lymphotropic virus (STLV)-like infection were reported in healthy persons exposed to nonhuman primates (NHPs) in West-Central Africa, less is known about the distribution of these viruses in Western Africa and in hospitalized populations. We serologically screened for SFV and STLV infection using 1,529 specimens collected between 1985 and 1997 from Cote d'Ivoire patients with high HIV prevalence. PCR amplification and analysis of SFV, STLV, and HIV/SIV sequences from PBMCs was used to investigate possible Simian origin of infection. We confirmed SFV antibodies in three persons (0.2%), two of whom were HIV-1-infected. SFV polymerase (pol) and LTR sequences were detected in PBMC DNA available for one HIV-infected person. Phylogenetic comparisons with new SFV sequences from African guenons showed infection likely originated from a Chlorocebus sabaeus monkey endemic to Cote d'Ivoire. 4.6% of persons were HTLV seropositive and PCR testing of PBMCs from 15 HTLV seroreactive persons identified nine with HTLV-1 and one with HTLV-2 LTR sequences. Phylogenetic analysis showed that two persons had STLV-1-like infections, seven were HTLV-1, and one was an HTLV-2 infection. 310/858 (53%), 8/858 (0.93%), and 18/858 (2.1%) were HIV-1, HIV-2, and HIV-positive but undifferentiated by serology, respectively. No SIV sequences were found in persons with HIV-2 antibodies (n = 1) or with undifferentiated HIV results (n = 7). We document SFV, STLV-1-like, and dual SFV/HIV infection in Cote d'Ivoire expanding the geographic range for zoonotic Simian Retrovirus transmission to West Africa. These findings highlight the need to define the public health consequences of these infections. Studying dual HIV-1/SFV infections in immunocompromised populations may provide a new opportunity to better understand SFV pathogenicity and transmissibility in humans.
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nonhuman primate Retroviruses from cambodia high Simian foamy virus prevalence identification of divergent stlv 1 strains and no evidence of siv infection
Infection Genetics and Evolution, 2013Co-Authors: Ahidjo Ayouba, William M. Switzer, Linda Duval, Florian Liegeois, Sopheak Ngin, Steve Ahukamundeke, Eric Delaporte, Frederic Ariey, Martine Peeters, Eric NerrienetAbstract:Abstract Nonhuman primates (NHPs) carry Retroviruses such as Simian immunodeficiency viruses (SIV), Simian T-cell lymphotropic viruses (STLV) and Simian foamy viruses (SFV). Here, we revisited NHPs from Cambodia to assess the prevalence and diversity of these Retroviruses using updated viral detection tools. We screened blood from 118 NHPs consisting of six species (Macaca fascicularis (n = 91), Macaca leonine (n = 8), Presbytis cristata (n = 3), Nycticebus coucang (n = 1), Hylobates pileatus (n = 14), and Pongo pygmaeus) (n = 1) by using a Luminex-based multiplex serology assay that allows the detection of all known SIV/HIV and SFV lineages. We also used highly sensitive PCR assays to detect each Simian Retrovirus group. Positive PCR products were sequenced and phylogenetically analyzed to infer evolutionary histories. Fifty-three of 118 (44.9%) NHPs tested positive for SFV by serology and 8/52 (15.4%), all from M. fascicularis, were PCR-confirmed. The 8 novel SFV sequences formed a highly supported distinct lineage within a clade composed of other macaque SFV. We observed no serological or molecular evidence of SIV infection among the 118 NHP samples tested. Four of 118 (3.3%) NHPs were PCR-positive for STLV, including one M. fascicularis, one P. cristata, and two H. pileatus. Phylogenetic analyses revealed that the four novel STLV belonged to the PTLV-1 lineage, outside the African radiation of PTLV-1, like all Asian PTLV identified so far. Sequence analysis of the whole STLV-1 genome from a H. pileatus (C578_Hp) revealed a genetic structure characteristic of PTLV. Similarity analysis comparing the STLV-1 (C578_Hp) sequence with prototype PTLVs showed that C578_Hp is closer to PTLV-1s than to all other types across the entire genome. In conclusion, we showed a high frequency of SFV infection but found no evidence of SIV infection in NHPs from Cambodia. We identified for the first time STLV-1 in a P. cristata and in two H. pileatus.
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naturally acquired Simian Retrovirus infections in central african hunters
The Lancet, 2004Co-Authors: Nathan D Wolfe, William M. Switzer, Jean K Carr, Vinod Bhullar, Vedapuri Shanmugam, Ubald Tamoufe, Tassy A Prosser, Judith N Torimiro, Anthony Wright, Eitel MpoudingoleAbstract:Summary Background Hunting and butchering of wild non-human primates infected with Simian immunodeficiency virus (SIV) is thought to have sparked the HIV pandemic. Although SIV and other primate Retroviruses infect laboratory workers and zoo workers, zoonotic Retrovirus transmission has not been documented in natural settings. We investigated zoonotic infection in individuals living in central Africa. Methods We obtained behavioural data, plasma samples, and peripheral blood lymphocytes from individuals living in rural villages in Cameroon. We did serological testing, PCR, and sequence analysis to obtain evidence of Retrovirus infection. Findings Zoonotic infections with Simian foamy virus (SFV), a Retrovirus endemic in most Old World primates, were identified in people living in central African forests who reported direct contact with blood and body fluids of wild non-human primates. Ten (1%) of 1099 individuals had antibodies to SFV. Sequence analysis from these individuals revealed three geographicallyindependent human SFV infections, each of which was acquired from a distinct non-human primate lineage: De Brazza’s guenon (Cercopithecus neglectus), mandrill (Mandrillus sphinx), and gorilla (Gorilla gorilla), two of which (De Brazza’s guenon and mandrill) are naturally infected with SIV. Interpretation Our findings show that Retroviruses are actively crossing into human populations, and demonstrate that people in central Africa are currently infected with SFV. Contact with non-human primates, such as happens during hunting and butchering, can play a part in the emergence of human Retroviruses and the reduction of primate bushmeat hunting has the potential to decrease the frequency of disease emergence.