RESEARCH Open Access Heterogeneous susceptibility of circulating .Heterogeneous susceptibility of
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Mamede et al. Retrovirology 2013, 10:77http://www.retrovirology.com/content/10/1/77
RESEARCH Open Access
Heterogeneous susceptibility of circulating SIVisolate capsids to HIV-interacting factorsJoo I Mamede1,2,3, Marc Sitbon1,2,3, Jean-Luc Battini1,2,3 and Valrie Courgnaud1,2,3*
Background: Many species of non-human primates in Africa are naturally infected by simian immunodeficiencyviruses (SIV) and humans stand at the forefront of exposure to these viruses in Sub-Saharan Africa. Cross-speciestransmission and adaptation of SIV to humans have given rise to human immunodeficiency viruses (HIV-1 and HIV-2)on twelve accountable, independent occasions. However, the determinants contributing to a simian-to-humanlasting transmission are not fully understood. Following entry, viral cores are released into the cytoplasm andbecome the principal target of host cellular factors. Here, we evaluated cellular factors likely to be involved inpotential new SIV cross-species transmissions. We investigated the interactions of capsids from naturally circulating SIVisolates with both HIV-1 restricting (i.e. TRIM5 proteins) and facilitating (i.e. cyclophilin A and nucleopore-associatedNup358/RanBP2 and Nup153) factors in single-round infectivity assays that reproduce early stages of the viral life-cycle.
Results: We show that human TRIM5 is unlikely to prevent cross-species transmission of any SIV we tested andobserved that the SIV CA-CypA interaction is a widespread but not a universal feature. Moreover, entry in the nucleus ofdifferent SIV appeared to follow pathways that do not necessarily recruit Nup358/RanBP2 or Nup153, and this regardlessof their interaction with CypA. Nevertheless, we found that, like HIV-1, human-adapted HIV-2 infection was dependent onNup358/RanBP2 and Nup153 interactions for optimal infection. Furthermore, we found that, unlike HIV CA, SIV CA did notrequire a direct interaction with the Cyp-like domain of Nup358/RanBP2 to carry out successful infection.
Conclusions: Circulating SIV present a variety of phenotypes with regard to CA-interacting restricting or facilitatingfactors. Altogether, we unveiled unidentified pathways for SIV CA, which could also be exploited by HIV in differentcellular contexts, to drive entry into the nucleus. Our findings warrant a closer evaluation of other potential defensesagainst circulating SIV.
Keywords: HIV-1, HIV-2, SIV, TRIM5, TRIMCyp, Nup153, Nup358/RanBP2, Lentiviral capsids
BackgroundRetroviruses are known to overcome species barriers andthere is now significant evidence that the AIDS epidemicsresulted from several cross-species transmissions fromprimates to humans. Simian immunodeficiency viruses(SIV) form a large group of related viruses which arenaturally endemic to a wide variety of African nonhumanprimate species. To date, serological evidence of SIV in-fection has been reported in at least 45 Old World monkeyand ape species and partial or full-length viral sequences
* Correspondence: email@example.comInstitut de Gntique Molculaire de Montpellier UMR 5535 CNRS, 1919route de Mende, 34293, Montpellier cedex 5, France2Universit Montpellier 2, Place Eugne Bataillon, 34095, Montpellier cedex 5,FranceFull list of author information is available at the end of the article
2013 Mamede et al.; licensee BioMed CentrCommons Attribution License (http://creativecreproduction in any medium, provided the or
have been characterized from most of them . SIV havea long history of simian-to-simian transmissions [2-4]. Thus,the progenitor of the human immunodeficiency virus type 1(HIV-1), SIVcpz, isolated from chimpanzees, is a recom-binant virus derived from two viruses that infect Old Worldmonkey species . Moreover, at least 11 independentcross-species transmissions of SIV from chimpanzees (Pantroglodytes troglodytes) and sooty mangabeys (Cercocebusatys) to humans have given rise to HIV-1 and HIV-2, re-spectively [6-8]. More recently a twelfth independent trans-mission has been described with the isolation of a newgroup of HIV-1, P, in a Cameroonian woman. HIV-1 P isclosely related to an SIV found in gorillas (Gorilla gorilla)in the wild . Therefore, a large pool of SIV that arewidely distributed in Sub-Saharan Africa represents a po-tential risk for the exposed human population [10,11].
al Ltd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.
Mamede et al. Retrovirology 2013, 10:77 Page 2 of 15http://www.retrovirology.com/content/10/1/77
However, despite this high exposure to viruses, success-ful SIV cross-species infection remains rather rare sincethe majority of the SIV characterized so far, have noknown human counterparts. Nevertheless, little is knownabout the factors that can potentially contribute to, orrestrict, simian-to-human transmissions. The SIV tropismfor new species is determined by their ability to exploitparticular cellular host proteins for their replication whilecounteracting inhibiting factors. In primates, several clas-ses of retroviral cellular restrictions have been identifiedat different steps of the retroviral cycle, including cyti-dine deaminases (e.g. APOBEC3G) , CD317/tetherin[13,14], SAMHD1 [15,16] and TRIM5 proteins .Interestingly, it has been shown that all these proteinsdisplay signatures of positive selection throughout manyprimate lineages [18-21] indicative of an ongoing host/virus history.Following binding of virions to cellular receptors and
entry into the cell, the viral capsid (CA) is released intothe cytoplasm. Thus, CA constitutes an early target forhost cellular factors that are either required for lentivirusreplication or have anti-retroviral properties. One of theearliest identified post-entry restriction factors, TRIM5,acts before reverse transcription . TRIM5 is a mem-ber of the large family of tripartite motif proteins (TRIM)that contain RING, B-box, and coiled-coil domains withan additional C-terminal PRYSPRY domain, which isrequired for its antiretroviral activity . TRIM5 re-stricts retroviruses in a virus-specific and species-specificway. For example, rhesus monkey (rh) or African greenmonkey (agm) TRIM5 potently restricts HIV-1, whereashuman TRIM5 has no significant detectable effect onHIV-1; in contrast human TRIM5 potently restrictsN-tropic murine leukemia virus (N-MLV) [23-25], awidespread and phylogenetically very distant mousegammaretrovirus. Interestingly, it has recently been de-scribed that some HIV-2 strains are sensitive to humanTRIM5 . TRIM5 is a cellular E3 ubiquitin ligase,that recognizes incoming multimerized viral cores andaccelerates uncoating of retroviral capsids [27,28]. Morerecently, it has been described that TRIM5 can act as apattern recognition receptor (PRR), promoting innateimmune signaling in response to retroviral infection. The CA protein of HIV-1 also interacts with highaffinity to the host protein cyclophilin A (CypA) .CypA, encoded by the peptidyl prolyl isomerase A gene(PPIA), has been shown to be important for efficientHIV-1 replication either by promoting uncoating  orby protecting the CA from an unidentified restrictionfactor [32-34]. Intriguingly, in the New World owl monkeys(Aotus sp.), TRIM5 is replaced by TRIMCyp in which aCypA pseudogene is fused to the Linker 2 region, substi-tuting for the SPRY domain [35,36]. More recently, similarbut independent TRIM-Cyp gene fusions have been also
discovered in different species of Old World monkeys, suchas rhesus macaques (Macaca mulatta) and cynomolgusmacaques (Macaca fascicularis), highlighting the repro-ducible evolutionary advantages provided by this genefusion . Owl-TRIMCypA and mafa-TRIMCypA pro-teins were described to efficiently block HIV-1 infectionwhile mamu-TRIMCypA was shown to block infectionby HIV-2 . Therefore, CypA binding to viral CA isan evolutionary widespread feature and likely to be re-quired by multiple HIV/SIV lineages.Recently, large-scale RNA interference screens have re-
vealed numerous host protein factors influencing HIV-1infection, bringing to light potential new pathways in theviral life cycle [39-43]. In contrast to other retroviruses,lentiviruses have developed specific mechanisms for theproductive infection of non-dividing cells  and it hasbeen shown that the capsid plays an important role forthis property of HIV-1 [45-48]. Alhough the mechanismsused by the HIV-1 pre-integration complexes (PIC) toenter into the nucleus are not fully understood, a smalloverlap between independent screens highlight severalcritical co-factors known to play independently a rolein the nuclear import of the HIV-1 PIC [49-51]. Indeed,depletion of the nuclear pore complex component Nup153or the nuclear transport factor Nup358/RanBP2 hinderednuclear import of HIV-1 and SIVmac [52-55]. Additionaly,it has been shown that depletion of the karyopherintransportin 3 (TNPO3) strongly decreases the infectivityof HIV-1 through a specific block of integration followingnuclear import [53,56-58]. Nup153 and Nup358/RanBP2are present in nuclear pore complexes (NPC) and seem toactively regulate nuclear entry of viral PIC [45,54,57,59,60].Nup358/RanBP2, is located at the cytoplasmic side of thepore and has a C-terminal cyclophilin-like domain .Given that HIV-1 can interact directly with this domain,it has been hypothesized that this motif could be re-sponsible for the recognition of incoming capsids andthus mediating nuclear import [62,63].Most of the knowledge regarding successive steps in
lentiviral replication comes from studies using prototypicHIV-1 or SIVmac. However, much less is known on theintrinsic capabilities