The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4.
BACKGROUND
Viruses frequently render cells refractory to subsequent infection with the same virus. This state of superinfection immunity counteracts potentially detrimental consequences for the infected cell and facilitates high-level replication and viral spread in the host.


RESULTS
Here, we show that human immunodeficiency virus (HIV) employs its early gene product Nef to efficiently interfere with superinfection at the viral-entry step. In this context, we identify the downregulation of cell-surface CCR5, the major HIV coreceptor, as a novel and highly conserved activity of Nef. Nef targets the CCR5 coreceptor and the HIV binding receptor CD4 via distinct cellular machineries to enhance the endocytosis rate of both HIV receptor components and to accelerate their degradation. Functionally, these genetically separable actions by Nef synergized to efficiently protect cells from HIV superinfection at the level of fusion of the viral envelope with the plasma membrane.


CONCLUSIONS
HIV has evolved two independent activities for Nef to downregulate the receptor complex and to facilitate its efficient replication and spread. This evasion strategy likely represents a mechanism by which the pathogenicity factor Nef elevates viral replication in vivo and thus promotes AIDS pathogenesis.
Michel
Nico
N
Department of Virology, University of Heidelberg, Germany.
Allespach
Ina
I
Venzke
Stephanie
S
Fackler
Oliver T
OT
Keppler
Oliver T
OT
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism / Q000502:physiology; D016466:CHO Cells; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D004705:Endocytosis / Q000502:physiology; D005434:Flow Cytometry; D015693:Gene Products, nef / Q000276:immunology / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006678:HIV / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D019713:Receptors, CCR5 / Q000378:metabolism* / Q000502:physiology; D015163:Superinfection / Q000276:immunology* / Q000821:virology; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D018946:Chemokine CCL5; D015693:Gene Products, nef; D019713:Receptors, CCR5; D054311:nef Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins