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 ent ry into cells (X4-HIV) inefficiently transmit infection across mucosal surf aces [1], despite their presence in seminal fluid and mucosal secretions fr om infected individuals [2-4]. In addition, although intestinal lymphocytes are susceptible to infection with either X4-HIV particles or particles tha t use the chemokine receptor CCR5 for viral entry (R5-HIV) during ex vivo c ulture [5], only systemic inoculation of RE-chimeric simian-HIV (S-HIV) res ults in a rapid loss of CD4(+) intestinal lymphocytes in macaques [6]. The mechanisms underlying the inefficient capacity of X4-HIV to transmit infect ion across mucosal surfaces and to infect intestinal lymphocytes in vivo ha ve remained elusive. The CCR5 ligands RANTES, MIP-1 alpha and MIP-1 beta su ppress infection by R5-HIV-1 particles via Induction of CCR5 internalizatio n, and individuals whose peripheral blood lymphocytes produce high levels o f these chemokines are relatively resistant to infection [7-9]. Here, we sh ow that the CXCR4 ligand stromal derived factor-1 (SDF-1) is constitutively expressed by mucosal epithelial cells at sites of HIV transmission and pro pagation. Furthermore, CXCR4 is selectively downmodulated on intestinal lym phocytes within the setting of prominent SDF-1 expression. We postulate tha t mucosally derived SDF-1 continuously downmodulates CXCR4 on resident HIV target cells, thereby reducing the transmission and propagation of X4-HIV a t mucosal sites. Moreover, such a mechanism could contribute to the delayed emergence of X4 isolates, which predominantly occurs during the later stag es of the HIV infection.