Naturally Occurring Capsid Substitutions Render HIV-1 Cyclophilin A Independent in Human Cells and TRIM-cyclophilin-resistant in Owl Monkey Cells

Generation of human TRIM5α mutants with high HIV-1 restriction activity

“…61,62 However, it has been suggested that cyclophilin A-independent strains of HIV-1 are circulating among patients. 63 The advantage of the mutant TRIM5a hu approach, on the other hand, lies in its plasticity: additional TRIM5a hu mutants with anti-HIV-1 activity could be found in different and largerscale mutagenic screens than the one described here, and the search for variants that do not lead to the appearance of resistant HIV-1 strains could be fully integrated in this discovery process.…”

Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors

“…A recent study by Chatterji et al 17 reported that certain HIV-1 variants from the main group can replicate in human cells in a CypA-independent manner. Normally, HIV-1 relies on the CypA cytoplasmic protein to facilitate early stages of viral infection.…”

“…These triple and quadruple capsid mutant viruses were also more efficient at transducing OMK cells, which are derived from a new world monkey species that shows restricted HIV-1 infection. 17 We decided to further study the effects of these particular capsid sequence mutations on lentiviral transduction of both human and non-human primate tissues by introducing the three or four aminoacid substitutions in the CypA-binding site of the Gag protein for an HIV-1-derived lentiviral vector packaging plasmid ( Figure 2). To assess the transduction efficiency of HIV-1 vectors packaged with Gag proteins bearing the capsid mutations, the HIV-1 capsid quadruple mutant vector (HIV quad ) was titrated side by side with standard HIV-1-and SIV-derived lentiviral vectors on cell lines derived from both human and non-human primates.…”

“…16 Some naturally occurring HIV-1 isolates can replicate in a CypAindependent manner in human cells, a phenotype that is caused by specific amino-acid substitutions in the CypA-binding region of the viral capsid. 17 Interestingly, mutation of four specific amino-acid residues in this region can also in part overcome TRIM-Cyp restriction in OMK cells. 17 Both human and non-human primate CD34 + hematopoietic cells are important target cells for lentiviral gene transfer studies.…”

“…17 Interestingly, mutation of four specific amino-acid residues in this region can also in part overcome TRIM-Cyp restriction in OMK cells. 17 Both human and non-human primate CD34 + hematopoietic cells are important target cells for lentiviral gene transfer studies. In previous work, we utilized SIVderived lentiviral vectors to transduce rhesus macaque CD34 + hematopoietic stem cells in a model of autologous stem cell transplantation.…”