title: Mycobacterium tuberculosis-induced CXCR4 and chemokine expression leads to preferential X4 HIV-1 replication in human macrophages.
abstract: Opportunistic infections such as pulmonary tuberculosis (TB) increase local HIV-1 replication and mutation. As AIDS progresses, alteration of the HIV-1 gp120 V3 sequence is associated with a shift in viral coreceptor use from CCR5 (CD195) to CXCR4 (CD184). To better understand the effect of HIV/TB coinfection, we screened transcripts from bronchoalveolar lavage cells with high density cDNA arrays and found that CXCR4 mRNA is increased in patients with TB. Surprisingly, CXCR4 was predominately expressed on alveolar macrophages (AM). Mycobacterium tuberculosis infection of macrophages in vitro increased CXCR4 surface expression, whereas amelioration of disease reduced CXCR4 expression in vivo. Bronchoalveolar lavage fluid from TB patients had elevated levels of CCL4 (macrophage inflammatory protein-1beta), CCL5 (RANTES), and CX3CL1 (fractalkine), but not CXCL12 (stromal-derived factor-1alpha). We found that M. tuberculosis infection of macrophages in vitro increased viral entry and RT of CXCR4-using [corrected] HIV-1, but not of CCR5-using [corrected] HIV-1. Lastly, HIV-1 derived from the lung contains CD14, suggesting that they were produced in AM. Our results demonstrate that TB produces a permissive environment for replication of CXCR4-using virus by increasing CXCR4 expression in AM and for suppression of CCR5-using HIV-1 by increasing CC chemokine expression. These changes explain in part why TB accelerates the course of AIDS. CXCR4 inhibitors are a rational therapeutic approach in HIV/TB coinfection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. hoshiy01@gcrc.med.nyu.edu
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Doris B
authors.initials: DB
authors.lastname: Tse
authors.forename: Gemma
authors.initials: G
authors.lastname: Rochford
authors.forename: Savita
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Satomi
authors.initials: S
authors.lastname: Hoshino
authors.forename: Nishay
authors.initials: N
authors.lastname: Chitkara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kuwabara
authors.forename: Elbert
authors.initials: E
authors.lastname: Ching
authors.forename: Bindu
authors.initials: B
authors.lastname: Raju
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Gold
authors.forename: William
authors.initials: W
authors.lastname: Borkowsky
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
authors.forename: Michael
authors.initials: M
authors.lastname: Weiden
mesh_terms: D000595:Amino Acid Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020523:Chemokines, CX3C / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009894:Opportunistic Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000096:biosynthesis; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000502:physiology; D013045:Species Specificity; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000821:virology; D015854:Up-Regulation / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
chemical_list: C515354:CCR4 protein, human; D019742:Chemokines, CC; D020523:Chemokines, CX3C; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019707:Receptors, Chemokine