HIV-1 Uses Dynamic Podosomes for Entry into Macrophages

Abstract

ABSTRACT Macrophages are one of the major targets of human immunodeficiency virus 1 (HIV-1) and play crucial roles in viral dissemination and persistence during AIDS progression. Here, we reveal the dynamic podosome-mediated entry of HIV-1 into macrophages. Inhibition of podosomes prevented HIV-1 entry into macrophages, while stimulation of podosome formation promoted viral entry. Single-virus tracking revealed the temporal and spatial mechanism of the dynamic podosome-mediated viral entry process. The core and ring structures of podosomes played complex roles in viral entry. The HIV coreceptor CCR5 was recruited to form specific clusters at the podosome ring, where it participated in viral entry. The podosome facilitated HIV-1 entry with a rotation mode triggered by dynamic actin. Our discovery of this novel HIV-1 entry route into macrophages, mediated by podosomes critical for cell migration and tissue infiltration, provides a new view of HIV infection and pathogenesis, which may assist in the development of new antiviral strategies. IMPORTANCE Macrophages are motile leukocytes and play critical roles in HIV-1 infection and AIDS progression. Podosomes, as small dynamic adhesion microdomains driven by the dynamic actin cytoskeleton, are mainly involved in cell migration of macrophages. Herein, we found that HIV-1 uses dynamic podosomes to facilitate its entry into macrophages. Single-virus imaging coupled with drug assays revealed the mechanism underlying the podosome-mediated route of HIV-1 entry into macrophages, including the dynamic relationship between the viral particles and the podosome core and ring structures, the CCR5 coreceptor. The dynamic podosome-mediated entry of HIV-1 into macrophages will be very significant for HIV-1 pathogenesis, especially for viral dissemination via macrophage migration and tissue infiltration. Thus, we report a novel HIV-1 entry route into macrophages mediated by podosomes, which extends our understanding of HIV infection and pathogenesis.