title: Lv4 Is a Capsid-Specific Antiviral Activity in Human Blood Cells That Restricts Viruses of the SIVMAC/SIVSM/HIV-2 Lineage Prior to Integration.
abstract: HIV-2 and SIVMAC are AIDS-causing, zoonotic lentiviruses that jumped to humans and rhesus macaques, respectively, from SIVSM-bearing sooty mangabey monkeys. Cross-species transmission events such as these sometimes necessitate virus adaptation to species-specific, host restriction factors such as TRIM5. Here, a new human restriction activity is described that blocks viruses of the SIVSM/SIVMAC/HIV-2 lineage. Human T, B, and myeloid cell lines, peripheral blood mononuclear cells and dendritic cells were 4 to >100-fold less transducible by VSV G-pseudotyped SIVMAC, HIV-2, or SIVSM than by HIV-1. In contrast, transduction of six epithelial cell lines was equivalent to that by HIV-1. Substitution of HIV-1 CA with the SIVMAC or HIV-2 CA was sufficient to reduce HIV-1 transduction to the level of the respective vectors. Among such CA chimeras there was a general trend such that CAs from epidemic HIV-2 Group A and B isolates were the most infectious on human T cells, CA from a 1° sooty mangabey isolate was the least infectious, and non-epidemic HIV-2 Group D, E, F, and G CAs were in the middle. The CA-specific decrease in infectivity was observed with either HIV-1, HIV-2, ecotropic MLV, or ALV Env pseudotypes, indicating that it was independent of the virus entry pathway. As2O3, a drug that suppresses TRIM5-mediated restriction, increased human blood cell transduction by SIVMAC but not by HIV-1. Nonetheless, elimination of TRIM5 restriction activity did not rescue SIVMAC transduction. Also, in contrast to TRIM5-mediated restriction, the SIVMAC CA-specific block occurred after completion of reverse transcription and the formation of 2-LTR circles, but before establishment of the provirus. Transduction efficiency in heterokaryons generated by fusing epithelial cells with T cells resembled that in the T cells, indicative of a dominant-acting SIVMAC restriction activity in the latter. These results suggest that the nucleus of human blood cells possesses a restriction factor specific for the CA of HIV-2/SIVMAC/SIVSM and that cross-species transmission of SIVSM to human T cells necessitated adaptation of HIV-2 to this putative restriction factor.
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland; Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pizzato
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Sean Matthew
authors.initials: SM
authors.lastname: McCauley
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Martha R
authors.initials: MR
authors.lastname: Neagu
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Firrito
authors.affiliation: Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ziglio
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Dauphin
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Zufferey
authors.affiliation: Laboratory of Retrovirology, University of Québec, Trois-Rivières, Quebec, Canada.
authors.forename: Lionel
authors.initials: L
authors.lastname: Berthoux
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Luban
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000382:microbiology*; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000821:virology; D015498:HIV-2 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D016662:Virus Integration / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents