Monkey Gene That Blocks AIDS Viruses Evolved More Than Once

[HAL 9000 96]

Monkey Gene That Blocks AIDS Viruses Evolved More Than Once

2 hours, 38 minutes ago

FRIDAY, Feb. 29 (HealthDay News) -- A gene in Asian monkeys that may have evolved as protection against a group of viruses that includes HIV has been identified by Harvard Medical School researchers, who add that their finding suggests the current AIDS epidemic is not a new kind of scourge.

The TRIM5-CypA gene found in Asian macaques is a hybrid of two existing proteins, TRIM5 and CypA. This combination creates a single protein that blocks infections by lentiviruses.

This is the second time a TRIM5-CypA hybrid gene has been identified in monkeys. The other one -- TRIMCyp -- was found in South American owl monkeys in 2004. But it's not likely that these two gene combinations arose from a single common ancestor, the Harvard researchers said.

TRIM5-CypA wasn't found in monkey closely related to the Asian macaques and TRIMCyp wasn't found in any other South American primate species. This suggests that the two combination genes evolved separately, once in the macaques and once in the owl monkeys.

This development of similar genetic adaptations in different species is called convergent evolution. A prime example is the development of flight in bats and in birds.

The fact that adaptations involving TRIM5 and CypA occurred at least twice in primates suggests that this combination provided a strong evolutionary advantage, the Harvard researchers said.

It may be possible that the combination genes developed to prevent infection by prehistoric viruses related to modern HIV, they suggested. If this is true, it could mean that an AIDS-like epidemic is not unique to the current time, and such outbreaks may have afflicted the primate ancestors of humans.

The study is published in the Feb. 29 issue of PLoS Pathogens.

News Link

PNAS and J Virol also have several versions of similar research:

Proc Natl Acad Sci U S A. 2008 Feb 19 [Epub ahead of print]

Related Articles, Links

Click here to read

Independent evolution of an antiviral TRIMCyp in rhesus macaques.

Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ.

Medical Research Council Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College Medical School, University College London, London W1T 4JF, United Kingdom;

The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIM5 genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIM5 protein in which the antiviral determinants in the B30.2 domain have been replaced by cyclophilin A (CypA) encoded by a retrotransposed cDNA. The owl monkey TRIMCyp protein restricts infection by a subset of lentiviruses that recruit CypA to their capsids, including HIV-1 and feline immunodeficiency virus. Here, we show that the Old World monkey, rhesus macaque (Macaca mulatta), also encodes a TRIMCyp protein that has arisen independently from that in owl monkeys. The rhesus TRIMCyp is encoded by a single, but common, allele (Mamu7) of the rhesus TRIM5 gene, among at least six further alleles that encode full-length TRIM5 proteins with no homology to CypA. The antiviral specificity of the rhesus TRIMCyp is distinct, restricting infection of HIV-2 and feline immunodeficiency virus but not HIV-1. Restriction by rhesus TRIMCyp is before reverse transcription and inhibited by blocking CypA binding, with cyclosporine A, or by mutation of the capsid CypA binding site. These observations suggest a mechanism of restriction that is conserved between TRIMCyp proteins. The lack of activity against HIV-1 suggests that Mamu7 homozygous animals will be null for TRIM5-mediated restriction of HIV-1 and could contribute to improved animal models for HIV/AIDS.

PMID: 18287035 [PubMed - as supplied by publisher]

2: Proc Natl Acad Sci U S A. 2008 Feb 19 [Epub ahead of print]

Related Articles, Links

Click here to read

Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species.

Virgen CA, Kratovac Z, Bieniasz PD, Hatziioannou T.

Aaron Diamond AIDS Research Center and.

The host range of retroviruses is influenced by antiviral proteins such as TRIM5, a restriction factor that recognizes and inactivates incoming retroviral capsids. Remarkably, in Owl monkeys (omk), a cyclophilin A (CypA) cDNA has been transposed into the TRIM5 locus, resulting in the expression of a TRIM5-CypA fusion protein (TRIMCyp) that restricts retroviral infection based on the retroviral capsid-binding specificity of CypA. Here, we report that the seemingly improbable genesis of TRIMCyp has, in fact, occurred twice, and pigtailed macaques (pgt) express an independently generated TRIMCyp protein. The omkTRIMCyp and pgtTRIMCyp proteins restrict infection by several lentiviruses, but their specificities are distinguishable. Surprisingly, pgtTRIMCyp cannot bind to or restrict HIV-1 capsids as a consequence of a point mutation close to the Cyp:capsid-binding interface that was acquired during or after transposition of pgtCypA. However, the same mutation confers on pgtTRIMCyp the ability to restrict FIV in the presence of cyclosporin A, a drug that normally abolishes the interaction between pgtTRIMCyp or omkTRIMCyp and lentiviral capsids. Overall, an intuitively unlikely evolutionary event has, in fact, occurred at least twice in primates and represents a striking example of convergent evolution in divergent species.

PMID: 18287034 [PubMed - as supplied by publisher]

3: Proc Natl Acad Sci U S A. 2008 Feb 19 [Epub ahead of print]

Related Articles, Links

Click here to read

TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis.

Brennan G, Kozyrev Y, Hu SL.

Departments of Microbiology and.

Primates have evolved a variety of restriction factors that prevent retroviral replication. One such factor, TRIM5alpha, mediates a postentry restriction in many Old World primates. Among New World primates, Aotus trivirgatus exerts a similar early restriction mediated by TRIMCyp, a TRIM5-cyclophilin A (CypA) chimera resulting from a CypA retrotransposition between exons 7 and 8 of the TRIM5 gene. Macaca nemestrina do not express TRIM5alpha; therefore, we asked whether these animals and related Old World primates express TRIMCyp. RT-PCR of total RNA from M. nemestrina and Macaca fascicularis yielded three TRIMCyp amplification products, one of which is predicted to encode a TRIMCyp chimera containing a full-length CypA. Unlike A. trivirgatus, genomic sequencing of M. nemestrina and M. fascicularis identifies a CypA retrotransposition in the 3' untranslated region of the TRIM5 locus. There is approximately 78% homology between the predicted protein sequences of Old World and New World primate TRIMCyp, with most of the differences found in the TRIM5-derived sequence. Notably, exon 7 is absent from both M. nemestrina and M. fascicularis TRIMCyp. Neither M. nemestrina nor M. fascicularis TRIMCyp could restrict HIV-1 or simian immunodeficiency virus SIVmac in an in vitro infectivity assay. The discovery of TRIMCyp in both M. nemestrina and M. fascicularis indicates that TRIMCyp expression may be more common among Old World primates than previously believed. Convergent evolution of TRIMCyp in both Old World and New World primates suggests that TRIMCyp may have provided evolutionary advantages.

PMID: 18287033 [PubMed - as supplied by publisher]

4: J Virol. 2007 Sep;81(18):10055-63. Epub 2007 Jul 3.

Related Articles, Links

Click here to read Click here to read

Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses.

Schaller T, Ylinen LM, Webb BL, Singh S, Towers GJ.

MRC Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College London Medical School, 46 Cleveland Street, London, United Kingdom.

TRIM5alpha is a potent intracellular antiviral restriction factor governing species-specific retroviral replication. In the New World species owl monkey the coding region for the viral binding B30.2 domain of TRIM5alpha has been replaced by a cyclophilin A (CypA) pseudogene by retrotransposition. The resultant TRIM5-CypA fusion protein restricts human immunodeficiency virus type 1 (HIV-1), as well as feline immunodeficiency virus (FIV), by recruitment of the CypA domain to the incoming viral capsids. Infectivity is rescued by agents such as cyclosporine that disrupt CypA binding to its substrates. Mice encode an antiviral restriction factor called Fv1 (for Friend virus susceptibility gene 1), which is active against murine leukemia virus and related to endogenous gag sequences. Here we show that fusing CypA to Fv1 generates a restriction factor with the antiviral specificity of TRIMCyp but the antiviral properties of Fv1. Like TRIMCyp, Fv1-Cyp restricts HIV-1 and FIV and is sensitive to inhibition by cyclosporine. TRIM5alpha is known to have a short half-life and block infectivity before viral reverse transcription. We show that Fv1-Cyp has a long half-life and blocks after reverse transcription, suggesting that its longer half-life gives the restricted virus the opportunity to synthesize DNA, leading to a later block to infection. This notion is supported by the observation that infectivity of Fv1-Cyp restricted virus can be rescued by cyclosporine for several hours after infection, whereas virus restricted by TRIMCyp is terminally restricted after around 40 min. Intriguingly, the Fv1-Cyp-restricted HIV-1 generates closed circular viral DNA, suggesting that the restricted virus complex enters the nucleus.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 17609268 [PubMed - indexed for MEDLINE]

[HAL 9000 96]

Monkey Gene That Blocks AIDS Viruses Evolved More Than Once

2 hours, 38 minutes ago

FRIDAY, Feb. 29 (HealthDay News) -- A gene in Asian monkeys that may have evolved as protection against a group of viruses that includes HIV has been identified by Harvard Medical School researchers, who add that their finding suggests the current AIDS epidemic is not a new kind of scourge.

The TRIM5-CypA gene found in Asian macaques is a hybrid of two existing proteins, TRIM5 and CypA. This combination creates a single protein that blocks infections by lentiviruses.

This is the second time a TRIM5-CypA hybrid gene has been identified in monkeys. The other one -- TRIMCyp -- was found in South American owl monkeys in 2004. But it's not likely that these two gene combinations arose from a single common ancestor, the Harvard researchers said.

TRIM5-CypA wasn't found in monkey closely related to the Asian macaques and TRIMCyp wasn't found in any other South American primate species. This suggests that the two combination genes evolved separately, once in the macaques and once in the owl monkeys.

This development of similar genetic adaptations in different species is called convergent evolution. A prime example is the development of flight in bats and in birds.

The fact that adaptations involving TRIM5 and CypA occurred at least twice in primates suggests that this combination provided a strong evolutionary advantage, the Harvard researchers said.

It may be possible that the combination genes developed to prevent infection by prehistoric viruses related to modern HIV, they suggested. If this is true, it could mean that an AIDS-like epidemic is not unique to the current time, and such outbreaks may have afflicted the primate ancestors of humans.

The study is published in the Feb. 29 issue of PLoS Pathogens.

News Link

PNAS and J Virol also have several versions of similar research:

Proc Natl Acad Sci U S A. 2008 Feb 19 [Epub ahead of print]

Related Articles, Links

Click here to read

Independent evolution of an antiviral TRIMCyp in rhesus macaques.

Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ.

Medical Research Council Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College Medical School, University College London, London W1T 4JF, United Kingdom;

The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIM5 genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIM5 protein in which the antiviral determinants in the B30.2 domain have been replaced by cyclophilin A (CypA) encoded by a retrotransposed cDNA. The owl monkey TRIMCyp protein restricts infection by a subset of lentiviruses that recruit CypA to their capsids, including HIV-1 and feline immunodeficiency virus. Here, we show that the Old World monkey, rhesus macaque (Macaca mulatta), also encodes a TRIMCyp protein that has arisen independently from that in owl monkeys. The rhesus TRIMCyp is encoded by a single, but common, allele (Mamu7) of the rhesus TRIM5 gene, among at least six further alleles that encode full-length TRIM5 proteins with no homology to CypA. The antiviral specificity of the rhesus TRIMCyp is distinct, restricting infection of HIV-2 and feline immunodeficiency virus but not HIV-1. Restriction by rhesus TRIMCyp is before reverse transcription and inhibited by blocking CypA binding, with cyclosporine A, or by mutation of the capsid CypA binding site. These observations suggest a mechanism of restriction that is conserved between TRIMCyp proteins. The lack of activity against HIV-1 suggests that Mamu7 homozygous animals will be null for TRIM5-mediated restriction of HIV-1 and could contribute to improved animal models for HIV/AIDS.

PMID: 18287035 [PubMed - as supplied by publisher]

2: Proc Natl Acad Sci U S A. 2008 Feb 19 [Epub ahead of print]

Related Articles, Links

Click here to read

Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species.

Virgen CA, Kratovac Z, Bieniasz PD, Hatziioannou T.

Aaron Diamond AIDS Research Center and.

The host range of retroviruses is influenced by antiviral proteins such as TRIM5, a restriction factor that recognizes and inactivates incoming retroviral capsids. Remarkably, in Owl monkeys (omk), a cyclophilin A (CypA) cDNA has been transposed into the TRIM5 locus, resulting in the expression of a TRIM5-CypA fusion protein (TRIMCyp) that restricts retroviral infection based on the retroviral capsid-binding specificity of CypA. Here, we report that the seemingly improbable genesis of TRIMCyp has, in fact, occurred twice, and pigtailed macaques (pgt) express an independently generated TRIMCyp protein. The omkTRIMCyp and pgtTRIMCyp proteins restrict infection by several lentiviruses, but their specificities are distinguishable. Surprisingly, pgtTRIMCyp cannot bind to or restrict HIV-1 capsids as a consequence of a point mutation close to the Cyp:capsid-binding interface that was acquired during or after transposition of pgtCypA. However, the same mutation confers on pgtTRIMCyp the ability to restrict FIV in the presence of cyclosporin A, a drug that normally abolishes the interaction between pgtTRIMCyp or omkTRIMCyp and lentiviral capsids. Overall, an intuitively unlikely evolutionary event has, in fact, occurred at least twice in primates and represents a striking example of convergent evolution in divergent species.

PMID: 18287034 [PubMed - as supplied by publisher]

3: Proc Natl Acad Sci U S A. 2008 Feb 19 [Epub ahead of print]

Related Articles, Links

Click here to read

TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis.

Brennan G, Kozyrev Y, Hu SL.

Departments of Microbiology and.

Primates have evolved a variety of restriction factors that prevent retroviral replication. One such factor, TRIM5alpha, mediates a postentry restriction in many Old World primates. Among New World primates, Aotus trivirgatus exerts a similar early restriction mediated by TRIMCyp, a TRIM5-cyclophilin A (CypA) chimera resulting from a CypA retrotransposition between exons 7 and 8 of the TRIM5 gene. Macaca nemestrina do not express TRIM5alpha; therefore, we asked whether these animals and related Old World primates express TRIMCyp. RT-PCR of total RNA from M. nemestrina and Macaca fascicularis yielded three TRIMCyp amplification products, one of which is predicted to encode a TRIMCyp chimera containing a full-length CypA. Unlike A. trivirgatus, genomic sequencing of M. nemestrina and M. fascicularis identifies a CypA retrotransposition in the 3' untranslated region of the TRIM5 locus. There is approximately 78% homology between the predicted protein sequences of Old World and New World primate TRIMCyp, with most of the differences found in the TRIM5-derived sequence. Notably, exon 7 is absent from both M. nemestrina and M. fascicularis TRIMCyp. Neither M. nemestrina nor M. fascicularis TRIMCyp could restrict HIV-1 or simian immunodeficiency virus SIVmac in an in vitro infectivity assay. The discovery of TRIMCyp in both M. nemestrina and M. fascicularis indicates that TRIMCyp expression may be more common among Old World primates than previously believed. Convergent evolution of TRIMCyp in both Old World and New World primates suggests that TRIMCyp may have provided evolutionary advantages.

PMID: 18287033 [PubMed - as supplied by publisher]

4: J Virol. 2007 Sep;81(18):10055-63. Epub 2007 Jul 3.

Related Articles, Links

Click here to read Click here to read

Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses.

Schaller T, Ylinen LM, Webb BL, Singh S, Towers GJ.

MRC Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College London Medical School, 46 Cleveland Street, London, United Kingdom.

TRIM5alpha is a potent intracellular antiviral restriction factor governing species-specific retroviral replication. In the New World species owl monkey the coding region for the viral binding B30.2 domain of TRIM5alpha has been replaced by a cyclophilin A (CypA) pseudogene by retrotransposition. The resultant TRIM5-CypA fusion protein restricts human immunodeficiency virus type 1 (HIV-1), as well as feline immunodeficiency virus (FIV), by recruitment of the CypA domain to the incoming viral capsids. Infectivity is rescued by agents such as cyclosporine that disrupt CypA binding to its substrates. Mice encode an antiviral restriction factor called Fv1 (for Friend virus susceptibility gene 1), which is active against murine leukemia virus and related to endogenous gag sequences. Here we show that fusing CypA to Fv1 generates a restriction factor with the antiviral specificity of TRIMCyp but the antiviral properties of Fv1. Like TRIMCyp, Fv1-Cyp restricts HIV-1 and FIV and is sensitive to inhibition by cyclosporine. TRIM5alpha is known to have a short half-life and block infectivity before viral reverse transcription. We show that Fv1-Cyp has a long half-life and blocks after reverse transcription, suggesting that its longer half-life gives the restricted virus the opportunity to synthesize DNA, leading to a later block to infection. This notion is supported by the observation that infectivity of Fv1-Cyp restricted virus can be rescued by cyclosporine for several hours after infection, whereas virus restricted by TRIMCyp is terminally restricted after around 40 min. Intriguingly, the Fv1-Cyp-restricted HIV-1 generates closed circular viral DNA, suggesting that the restricted virus complex enters the nucleus.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 17609268 [PubMed - indexed for MEDLINE]

Sorry to post duplicate topic.

[w¡n9Nµ7 §£@¥€r 123]

You do know that evolution is communist propaganda, don't you?

Edited February 29, 2008 by VJ Troll

[HAL 9000 96]

LOL...

[mawilson 2,133]

Who are you calling a monkey?

[mawilson 2,133]

Double post?

[HAL 9000 96]

Yeah, sorry.

[HAL 9000 96]

Disclaimer:

No Monkeys were shocked in the research described above.

I think at the least, an antiviral treatment could be developed based on this fusion protein by translating it into an industrial, mass-produced setting where E.coli creates tankfulls of the stuff. And the cost could be driven down given the mode of production.

However, such a therapy would not prevent infection but rather prevent reinfection by HIV within the same patient. A vaccine approach may be more feasible since it could potentially act as a barrier to infection by HIV in the first place. The approach could be taken also with FIV in kitties.

[Jason-Sasha 1]

Perhaps this will bring some real hope for a vaccine. It's long overdue.

[HAL 9000 96]

The point would be to make this fusion protein target viral proteins that are not prone to automutagenesis so as to avoid the HIV pullig a fast one on the host during the course of infection OR to make it a part of the host immune system's repertoire of antibodies so as to rapidly recognize HIV as HIV upon initial infection and destroy the darn thing from the beginning. The second approach is more interesting but mechanistically much more daunting to resolve... but not impossible.

[sj5 4]