title: Primary human immunodeficiency virus type 2 (HIV-2) isolates infect CD4-negative cells via CCR5 and CXCR4: comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo.
abstract: Cell surface receptors exploited by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) for infection are major determinants of tropism. HIV-1 usually requires two receptors to infect cells. Gp120 on HIV-1 virions binds CD4 on the cell surface, triggering conformational rearrangements that create or expose a binding site for a seven-transmembrane (7TM) coreceptor. Although HIV-2 and SIV strains also use CD4, several laboratory-adapted HIV-2 strains infect cells without CD4, via an interaction with the coreceptor CXCR4. Moreover, the envelope glycoproteins of SIV of macaques (SIV(MAC)) can bind to and initiate infection of CD4(-) cells via CCR5. Here, we show that most primary HIV-2 isolates can infect either CCR5(+) or CXCR4(+) cells without CD4. The efficiency of CD4-independent infection by HIV-2 was comparable to that of SIV, but markedly higher than that of HIV-1. CD4-independent HIV-2 strains that could use both CCR5 and CXCR4 to infect CD4(+) cells were only able to use one of these receptors in the absence of CD4. Our observations therefore indicate (i) that HIV-2 and SIV envelope glycoproteins form a distinct conformation that enables contact with a 7TM receptor without CD4, and (ii) the use of CD4 enables a wider range of 7TM receptors to be exploited for infection and may assist adaptation or switching to new coreceptors in vivo. Primary CD4(-) fetal astrocyte cultures expressed CXCR4 and supported replication by the T-cell-line-adapted ROD/B strain. Productive infection by primary X4 strains was only triggered upon treatment of virus with soluble CD4. Thus, many primary HIV-2 strains infect CCR5(+) or CXCR4(+) cell lines without CD4 in vitro. CD4(-) cells that express these coreceptors in vivo, however, may still resist HIV-2 entry due to insufficient coreceptor concentration on the cell surface to trigger fusion or their expression in a conformation nonfunctional as a coreceptor. Our study, however, emphasizes that primary HIV-2 strains carry the potential to infect CD4(-) cells expressing CCR5 or CXCR4 in vivo.
authors.affiliation: The Wohl Virion Centre, Department of Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, London, United Kingdom. j.reeves@ucl.ac.uk
authors.forename: J D
authors.initials: JD
authors.lastname: Reeves
authors.forename: S
authors.initials: S
authors.lastname: Hibbitts
authors.forename: G
authors.initials: G
authors.lastname: Simmons
authors.forename: A
authors.initials: A
authors.lastname: McKnight
authors.forename: J M
authors.initials: JM
authors.lastname: Azevedo-Pereira
authors.forename: J
authors.initials: J
authors.lastname: Moniz-Pereira
authors.forename: P R
authors.initials: PR
authors.lastname: Clapham
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000821:virology; D015704:CD4 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D015497:HIV-1 / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D015498:HIV-2 / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D015704:CD4 Antigens; D019713:Receptors, CCR5; D019718:Receptors, CXCR4