Ancuta Petronela, Autissier Patrick, Wurcel Alysse, Zaman Tauheed, Stone David, Gabuzda Dana
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
J Immunol. 2006 May 15;176(10):5760-71. doi: 10.4049/jimmunol.176.10.5760.
The CD16(+) monocyte (Mo) subset produces proinflammatory cytokines and is expanded in peripheral blood during progression to AIDS, but its contribution to HIV pathogenesis is unclear. In this study, we investigate the capacity of human CD16(+) and CD16(-) Mo subsets to render resting CD4(+) T cells permissive for HIV replication. We demonstrate that CD16(+) Mo preferentially differentiate into macrophages (Mphi) that activate resting T cells for productive HIV infection by producing the CCR3 and CCR4 ligands CCL24, CCL2, CCL22, and CCL17. CD16(+), but not CD16(-), Mo-derived Mphi from HIV-infected and -uninfected individuals constitutively produce CCL24 and CCL2. Furthermore, these chemokines stimulate HIV replication in CD16(-) Mo:T cell cocultures. Engagement of CCR3 and CCR4 by CCL24 and CCL2, respectively, along with stimulation via CD3/CD28, renders T cells highly permissive for productive HIV infection. Moreover, HIV replicates preferentially in CCR3(+) and CCR4(+) T cells. These findings reveal a new pathway of T cell costimulation for increased susceptibility to HIV infection via engagement of CCR3 and CCR4 by chemokines constitutively produced by CD16(+) Mo/Mphi. Thus, expansion of CD16(+) Mo in peripheral blood of HIV-infected patients and their subsequent recruitment into tissues may contribute to chronic immune activation and establishment of viral reservoirs in resting T cells.
CD16(+)单核细胞（Mo）亚群可产生促炎细胞因子，并且在进展为艾滋病期间在外周血中扩增，但其对HIV发病机制的作用尚不清楚。在本研究中，我们调查了人类CD16(+)和CD16(-) Mo亚群使静息CD4(+) T细胞对HIV复制具有易感性的能力。我们证明，CD16(+) Mo优先分化为巨噬细胞（Mphi），这些巨噬细胞通过产生CCR3和CCR4配体CCL24、CCL2、CCL22和CCL17来激活静息T细胞以进行有效的HIV感染。来自HIV感染和未感染个体的CD16(+)而非CD16(-) Mo衍生的Mphi组成性地产生CCL24和CCL2。此外，这些趋化因子可刺激CD16(-) Mo:T细胞共培养物中的HIV复制。CCL24和CCL2分别与CCR3和CCR4结合，以及通过CD3/CD28刺激，可使T细胞对有效的HIV感染具有高度易感性。此外，HIV优先在CCR3(+)和CCR4(+) T细胞中复制。这些发现揭示了一种新的T细胞共刺激途径，通过CD16(+) Mo/Mphi组成性产生的趋化因子与CCR3和CCR4结合，增加对HIV感染的易感性。因此，HIV感染患者外周血中CD16(+) Mo的扩增及其随后向组织中的募集可能有助于慢性免疫激活以及在静息T细胞中建立病毒储存库。
