title: Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation.
abstract: HIV particles that use the chemokine receptor CXCR4 as a coreceptor for entry into cells (X4-HIV) inefficiently transmit infection across mucosal surfaces [1], despite their presence in seminal fluid and mucosal secretions from infected individuals [2] [3] [4]. In addition, although intestinal lymphocytes are susceptible to infection with either X4-HIV particles or particles that use the chemokine receptor CCR5 for viral entry (R5-HIV) during ex vivo culture [5], only systemic inoculation of R5-chimeric simian-HIV (S-HIV) results in a rapid loss of CD4(+) intestinal lymphocytes in macaques [6]. The mechanisms underlying the inefficient capacity of X4-HIV to transmit infection across mucosal surfaces and to infect intestinal lymphocytes in vivo have remained elusive. The CCR5 ligands RANTES, MIP-1alpha and MIP-1beta suppress infection by R5-HIV-1 particles via induction of CCR5 internalization, and individuals whose peripheral blood lymphocytes produce high levels of these chemokines are relatively resistant to infection [7] [8] [9]. Here, we show that the CXCR4 ligand stromal derived factor-1 (SDF-1) is constitutively expressed by mucosal epithelial cells at sites of HIV transmission and propagation. Furthermore, CXCR4 is selectively downmodulated on intestinal lymphocytes within the setting of prominent SDF-1 expression. We postulate that mucosally derived SDF-1 continuously downmodulates CXCR4 on resident HIV target cells, thereby reducing the transmission and propagation of X4-HIV at mucosal sites. Moreover, such a mechanism could contribute to the delayed emergence of X4 isolates, which predominantly occurs during the later stages of the HIV infection.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Womens Hospital, Harvard Medical School, Boston 02115, USA. william.agace@immuno.lu.se
authors.forename: W W
authors.initials: WW
authors.lastname: Agace
authors.forename: A
authors.initials: A
authors.lastname: Amara
authors.forename: A I
authors.initials: AI
authors.lastname: Roberts
authors.forename: J L
authors.initials: JL
authors.lastname: Pablos
authors.forename: S
authors.initials: S
authors.lastname: Thelen
authors.forename: M
authors.initials: M
authors.lastname: Uguccioni
authors.forename: X Y
authors.initials: XY
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Marsal
authors.forename: F
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: T
authors.initials: T
authors.lastname: Delaunay
authors.forename: E C
authors.initials: EC
authors.lastname: Ebert
authors.forename: B
authors.initials: B
authors.lastname: Moser
authors.forename: C M
authors.initials: CM
authors.lastname: Parker
mesh_terms: D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology*; D006678:HIV / Q000254:growth & development*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019713:Receptors, CCR5; D019718:Receptors, CXCR4