Agace W W, Amara A, Roberts A I, Pablos J L, Thelen S, Uguccioni M, Li X Y, Marsal J, Arenzana-Seisdedos F, Delaunay T, Ebert E C, Moser B, Parker C M
Division of Rheumatology, Immunology and Allergy, Brigham and Womens Hospital, Harvard Medical School, Boston 02115, USA.
Curr Biol. 2000 Mar 23;10(6):325-8. doi: 10.1016/s0960-9822(00)00380-8.
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.
尽管利用趋化因子受体CXCR4作为进入细胞的共受体的HIV颗粒（X4-HIV）存在于受感染个体的精液和粘膜分泌物中[2][3][4]，但其跨粘膜表面传播感染的效率却很低[1]。此外，虽然在体外培养期间肠道淋巴细胞易受X4-HIV颗粒或利用趋化因子受体CCR5进行病毒进入的颗粒（R5-HIV）感染[5]，但只有全身接种R5嵌合猿猴-HIV（S-HIV）才会导致猕猴体内CD4(+)肠道淋巴细胞迅速减少[6]。X4-HIV跨粘膜表面传播感染以及在体内感染肠道淋巴细胞的低效能力背后的机制一直难以捉摸。CCR5配体RANTES、MIP-1α和MIP-1β通过诱导CCR5内化来抑制R5-HIV-1颗粒的感染，外周血淋巴细胞产生高水平这些趋化因子的个体对感染相对具有抗性[7][8][9]。在此，我们表明趋化因子受体CXCR4配体基质衍生因子-1（SDF-1）在HIV传播和扩散部位的粘膜上皮细胞中组成性表达。此外，在SDF-1表达显著的情况下，CXCR4在肠道淋巴细胞上被选择性下调。我们推测，粘膜来源的SDF-1持续下调驻留HIV靶细胞上的CXCR4，从而减少X4-HIV在粘膜部位的传播和扩散。此外，这种机制可能导致X4毒株的延迟出现，这主要发生在HIV感染的后期阶段。
