Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1

Abstract

In Old World primates, TRIM5-alpha confers a potent block to human immunodeficiency virus type 1 (HIV-1) infection that acts after virus entry into cells. Cyclophilin A (CypA) binding to viral capsid protects HIV-1 from a similar activity in human cells. Among New World primates, only owl monkeys exhibit post-entry restriction of HIV-1 (ref. 1). Paradoxically, the barrier to HIV-1 in owl monkey cells is released by capsid mutants or drugs that disrupt capsid interaction with CypA. Here we show that knockdown of owl monkey CypA by RNA interference (RNAi) correlates with suppression of anti-HIV-1 activity. However, reintroduction of CypA protein to RNAi-treated cells did not restore antiviral activity. A search for additional RNAi targets unearthed TRIMCyp, an RNAi-responsive messenger RNA encoding a TRIM5-CypA fusion protein. TRIMCyp accounts for post-entry restriction of HIV-1 in owl monkeys and blocks HIV-1 infection when transferred to otherwise infectable human or rat cells. It seems that TRIMCyp arose after the divergence of New and Old World primates when a LINE-1 retrotransposon catalysed the insertion of a CypA complementary DNA into the TRIM5 locus. This is the first vertebrate example of a chimaeric gene generated by this mechanism of exon shuffling.

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

“…TE activity can also indirectly generate beneficial novelties, by hijacking cellular mRNAs and catalyzing the insertion of their complementary DNA in new genomic environments. As an example, an advantageous fusion protein created through L1-induced mobilization of the cyclophilin A gene into the TRIM5 gene explains the resistance of the owl monkey to human immunodeficiency virus-1 infection (Sayah et al, 2004).…”

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

“…However, CsA concentrations used in other studies (2.5-5 mM) typically led to ablation of HIV-1 restriction in different non-human primate cell types. 8,9,16,17 Alternatively, it is possible that a cell-typespecific restriction exists that is not circumvented by either capsid mutations or CsA treatment. Kootstra et al 23 constructed an HIV-1 mutant vector with several amino-acid substitutions in the CypA-binding region that make the region more similar to the macrophagetropic Ba-L strain.…”

“…A special case exists in owl monkey (OMK) cells, where the gene for CypA apparently retrotransposed into the TRIM5 gene locus, replacing the SPRY domain. 9 CypA is thought to replace the capsid-binding function of the SPRY domain, and the resulting TRIM-Cyp factor potently restricts HIV-1. However, the correlation between the ability of a lentiviral capsid to bind CypA and restriction by simian TRIM5a is not absolute.…”

Intracellular trafficking of retroviral vectors: obstacles and advances

“…These cells contain an unusual TRIM5-Cyclophilin A (TRIMCypA)-fusion protein, arising from retrotransposition of a CypA pseudogene into the TRIM5a locus, replacing the TRIM5a SPRY domain for CypA. 103,104 TRIM-CypA restricts HIV-1 infection in owl monkey cells. 103,104 The CypA portion of TRIM-CypA also binds HIV-1 CA in vitro, 104 like human CypA binds HIV-1 CA.…”

“…103,104 TRIM-CypA restricts HIV-1 infection in owl monkey cells. 103,104 The CypA portion of TRIM-CypA also binds HIV-1 CA in vitro, 104 like human CypA binds HIV-1 CA. 105 This suggests the CypA portion of TRIM-CypA binds HIV-1 CA in vivo in place of the lost SPRY domain while the N-terminal TRIM motifs restrict virus infection.…”