Millan Ortiz

Publications (4)15.96 Total impact

• Article: Antiretroviral activity of ancestral TRIM5alpha.

  Valérie Goldschmidt, Angela Ciuffi, Millan Ortiz, David Brawand, Miguel Muñoz, Henrik Kaessmann, Amalio Telenti
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  ABSTRACT: The antiretroviral protein TRIM5alpha is known to have evolved different restriction capacities against various retroviruses, driven by positive Darwinian selection. However, how these different specificities have evolved in the primate lineages is not fully understood. Here we used ancestral protein resurrection to estimate the evolution of antiviral restriction specificities of TRIM5alpha on the primate lineage leading to humans. We used TRIM5alpha coding sequences from 24 primates for the reconstruction of ancestral TRIM5alpha sequences using maximum-likelihood and Bayesian approaches. Ancestral sequences were transduced into HeLa and CRFK cells. Stable cell lines were generated and used to test restriction of a panel of extant retroviruses (human immunodeficiency virus type 1 [HIV-1] and HIV-2, simian immunodeficiency virus [SIV] variants SIV(mac) and SIV(agm), and murine leukemia virus [MLV] variants N-MLV and B-MLV). The resurrected TRIM5alpha variant from the common ancestor of Old World primates (Old World monkeys and apes, approximately 25 million years before present) was effective against present day HIV-1. In contrast to the HIV-1 restriction pattern, we show that the restriction efficacy against other retroviruses, such as a murine oncoretrovirus (N-MLV), is higher for more recent resurrected hominoid variants. Ancestral TRIM5alpha variants have generally limited efficacy against HIV-2, SIV(agm), and SIV(mac). Our study sheds new light on the evolution of the intrinsic antiviral defense machinery and illustrates the utility of functional evolutionary reconstruction for characterizing recently emerged protein differences.
  Journal of Virology 04/2008; 82(5):2089-96. · 5.40 Impact Factor
• Source

  Available from: PubMed Central

  Article: Model structure of human APOBEC3G.

  Kun-Lin Zhang, Bastien Mangeat, Millan Ortiz, Vincent Zoete, Didier Trono, Amalio Telenti, Olivier Michielin
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  ABSTRACT: APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination. APOBEC3G has two cytosine deaminase (CDA) domains; the catalytically inactive amino-terminal domain of APOBEC3G (N-CDA) carries the Vif interaction domain. There is no 3-D structure of APOBEC3G solved by X-ray or nuclear magnetic resonance. We predicted the structure of human APOBEC3G based on the crystal structure of APOBEC2. To assess the model structure, we evaluated 48 mutants of APOBEC3G N-CDA that identify novel variants altering DeltaVif HIV-1 infectivity and packaging of APOBEC3G. Results indicated that the key residue D128 is exposed at the surface of the model, with a negative local electrostatic potential. Mutation D128K changes the sign of that local potential. In addition, two novel functionally relevant residues that result in defective APOBEC3G encapsidation, R122 and W127, cluster at the surface. The structure model identifies a cluster of residues important for packaging of APOBEC3G into virions, and may serve to guide functional analysis of APOBEC3G.
  PLoS ONE 02/2007; 2(4):e378. · 4.09 Impact Factor
• Source

  Available from: PubMed Central

  Article: Patterns of evolution of host proteins involved in retroviral pathogenesis.

  Millan Ortiz, Gabriela Bleiber, Raquel Martinez, Henrik Kaessmann, Amalio Telenti
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  ABSTRACT: BACKGROUND: Evolutionary analysis may serve as a useful approach to identify and characterize host defense and viral proteins involved in genetic conflicts. We analyzed patterns of coding sequence evolution of genes with known (TRIM5alpha and APOBEC3G) or suspected (TRIM19/PML) roles in virus restriction, or in viral pathogenesis (PPIA, encoding Cyclophilin A), in the same set of human and non-human primate species. RESULTS AND CONCLUSION: This analysis revealed previously unidentified clusters of positively selected sites in APOBEC3G and TRIM5alpha that may delineate new virus-interaction domains. In contrast, our evolutionary analyses suggest that PPIA is not under diversifying selection in primates, consistent with the interaction of Cyclophilin A being limited to the HIV-1M/SIVcpz lineage. The strong sequence conservation of the TRIM19/PML sequences among primates suggests that this gene does not play a role in antiretroviral defense.
  Retrovirology 02/2006; 3:11. · 6.47 Impact Factor
• Source

  Available from: Joke Snoeck

  Article: Activity of ancestral restriction factors against ancient retroviruses

  Nadia Rahm, Joke Snoeck, Millan Ortiz, Angela Ciuffi, Amalio Telenti