CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections

African green monkeys (AGM) and sooty mangabeys (SM) are well-studied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent s...

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Bibliographic Details
Published in:Journal of virology 2017-02, Vol.91 (4), p.e01626-16
Main Authors: Wetzel, Katherine S, Yi, Yanjie, Elliott, Sarah T C, Romero, Dino, Jacquelin, Beatrice, Hahn, Beatrice H, Muller-Trutwin, Michaela, Apetrei, Cristian, Pandrea, Ivona, Collman, Ronald G
Format: Article
Language:English
Subjects:
Animals
CD4-Positive T-Lymphocytes
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
CD4-Positive T-Lymphocytes - virology
Cellular Biology
Cercopithecus aethiops
Cloning, Molecular
Host-Pathogen Interactions
Human immunodeficiency virus 1
Lentivirus
Life Sciences
Lymphocytes
Lymphocytes - immunology
Lymphocytes - metabolism
Lymphocytes - virology
Microbiology and Parasitology
Pathogenesis and Immunity
Phylogeny
Receptors, CCR5
Receptors, CCR5 - genetics
Receptors, CCR5 - metabolism
Receptors, CCR6
Receptors, CCR6 - genetics
Receptors, CCR6 - metabolism
Receptors, Virus
Receptors, Virus - metabolism
Retroviridae
Sequence Analysis, DNA
Simian Acquired Immunodeficiency Syndrome
Simian Acquired Immunodeficiency Syndrome - immunology
Simian Acquired Immunodeficiency Syndrome - metabolism
Simian Acquired Immunodeficiency Syndrome - virology
Simian Immunodeficiency Virus
Simian Immunodeficiency Virus - classification
Simian Immunodeficiency Virus - physiology
Viral Envelope Proteins
Viral Envelope Proteins - genetics
Viral Envelope Proteins - metabolism
Viral Tropism
Virology
Virus Internalization
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Summary:African green monkeys (AGM) and sooty mangabeys (SM) are well-studied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent studies have shown that CCR5 is dispensable for SIV infection of SM in vivo and that blocking of CCR5 does not prevent ex vivo infection of peripheral blood mononuclear cells (PBMC) from SM or vervet AGM. In both hosts, CXCR6 is an efficient entry pathway in vitro Here we investigated the use of species-matched CXCR6 and other alternative coreceptors by SIVagmSab, which infects sabaeus AGM. We cloned sabaeus CD4 and 10 candidate coreceptors. Species-matched CXCR6, CCR5, and GPR15 mediated robust entry into transfected cells by pseudotypes carrying SIVagmSab92018ivTF Env, with lower-level entry through GPR1 and APJ. We cloned genetically divergent env genes from the plasma of two wild-infected sabaeus AGM and found similar patterns of coreceptor use. Titration experiments showed that CXCR6 and CCR5 were more efficient than other coreceptors when tested at limiting CD4/coreceptor levels. Finally, blocking of CXCR6 with its ligand CXCL16 significantly inhibited SIVagmSab replication in sabaeus PBMC and had a greater impact than did the CCR5 blocker maraviroc, confirming the use of CXCR6 in primary lymphocyte infection. These data suggest a new paradigm for SIV infection of natural host species, whereby a shared outcome of virus-host coevolution is the use of CXCR6 or other alternative coreceptors for entry, which may direct SIV toward CD4 T cell subsets and anatomical sites that support viral replication without disrupting immune homeostasis and function. Natural hosts of SIV do not progress to AIDS, in stark contrast to pathogenic human immunodeficiency virus type 1 (HIV-1)-human and SIVmac-macaque infections. Identifying how natural hosts avoid immunodeficiency can elucidate key mechanisms of pathogenesis. It is known that despite high viral loads, natural hosts have a low frequency of CD4 cells expressing the SIV coreceptor CCR5. In this study, we demonstrate the efficient use of the coreceptor CXCR6 by SIVagmSab to infect sabaeus African green monkey lymphocytes. In conjunction with studies of SIVsmm, which infects sooty mangabeys, and SIVagmVer, which infects vervet monkeys, our data suggest a unifying model whereby in natural hosts, in which the CCR5 expressio
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.01626-16