title: Adaptation of HIV-1 to rhTrim5α-mediated restriction in vitro.
abstract: Recently, gene therapy with rhTrim5α, an innate restriction factor which blocks HIV-1 at a post entry step, have been shown to be applicable as treatment in vitro. However, HIV-1 might adapt to replicate in the presence of rhTrim5α due to its high mutation rate. Here we observed that two different HIV-1 isolates were able to replicate in cells expressing high levels of rhTrim5α. Escape mutations were found in the conserved regions of the viral genome, Gag and p51 RT subunit. Furthermore, the escape mutations, predominantly in the capsid and p51 RT, altered viral sensitivity to modified huTrim5α R332P and R335G variants, with only a minor effect on the replication capacity in primary PBMCs. Therefore, gene therapy with rhTrim5α might be suitable for HIV-1 treatment, however the virus will eventually escape the pressure by gaining mutations in the conserved regions of the viral genome without any severe fitness cost.
authors.affiliation: Department of Experimental Immunology, Laboratory of Viral Immune and Pathogenesis at the Academic Medical Center of the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Laurentia C
authors.initials: LC
authors.lastname: Setiawan
authors.affiliation: Department of Experimental Immunology, Laboratory of Viral Immune and Pathogenesis at the Academic Medical Center of the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. Electronic address: N.A.Kootstra@amc.uva.nl.
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008253:Macaca mulatta / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D015683:Gene Products, gag; D011506:Proteins; D000070584:Tripartite Motif Proteins; D054302:pol Gene Products, Human Immunodeficiency Virus; C477346:TRIM5 protein, human; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases
keywords: Escape mutations; HIV-1; Reverse transcriptase; Trim5α; Viral capsid; Viral fitness