Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation.
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.
Agace
W W
WW
Division of Rheumatology, Immunology and Allergy, Brigham and Womens Hospital, Harvard Medical School, Boston 02115, USA. william.agace@immuno.lu.se
Amara
A
A
Roberts
A I
AI
Pablos
J L
JL
Thelen
S
S
Uguccioni
M
M
Li
X Y
XY
Marsal
J
J
Arenzana-Seisdedos
F
F
Delaunay
T
T
Ebert
E C
EC
Moser
B
B
Parker
C M
CM
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
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019713:Receptors, CCR5; D019718:Receptors, CXCR4