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CD16⁺ Monocyte-Derived Macrophages Activate Resting T Cells for HIV Infection by Producing CCR3 and CCR4 Ligands¹

Petronela Ancuta^*, Patrick Autissier, Alysse Wurcel, Tauheed Zaman, David Stone and Dana Gabuzda^2,*

^* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115; Beth Israel Deaconess Center, Boston, MA 02115; and Lemuel Shattuck Hospital, Jamaica Plain, MA 02130

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 (M) 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 M 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/M. 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.

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