HIV-1 infects macrophages by exploiting an endocytic route dependent on dynamin, Rac1 and Pak1.
Recent studies provide compelling evidence that HIV-1 entry in cell lines and lymphocytes proceeds by endocytosis, but these studies are still lacking in macrophages, an important natural target cell for HIV-1. Macrophages exhibit continual and extensive endocytic activity as part of their natural functions, so we investigated the uptake pathways involved in productive HIV-1 entry. We find that caveolae are not utilised by HIV-1, because the main structural proteins, caveolin-1 and 2 are absent from most human leukocytes. We then focused on macropinocytosis; we find that HIV-1 entry into macrophages is sensitive to inhibitors of Na(+)/H(+) exchange, actin rearrangement, dynamin, Rho family GTPases, and Pak1, but not to inhibitors of PI-3 kinase and myosin II. This leads us to conclude that HIV entry into macrophages proceeds by an endocytic pathway that is not classical macropinocytosis. Because of the limitations of a purely pharmacological study such as this, the final elucidation of this pathway awaits the development of reliable forward genetic approaches in authentic macrophages.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Gemma C
GC
Carter
Laura
L
Bernstone
Darshan
D
Baskaran
William
W
James
D002478:Cells, Cultured; D034281:Dynamins / Q000378:metabolism*; D004705:Endocytosis; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000502:physiology / Q000821:virology*; D053586:Virus Internalization; D054462:p21-Activated Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
C107953:RAC1 protein, human; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D034281:Dynamins