HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits.
Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.
Xu
Weifeng
W
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York, USA.
Santini
Paul A
PA
Sullivan
John S
JS
He
Bing
B
Shan
Meimei
M
Ball
Susan C
SC
Dyer
Wayne B
WB
Ketas
Thomas J
TJ
Chadburn
Amy
A
Cohen-Gould
Leona
L
Knowles
Daniel M
DM
Chiu
April
A
Sanders
Rogier W
RW
Chen
Kang
K
Cerutti
Andrea
A
D000199:Actins / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D019013:CD40 Antigens / Q000502:physiology; D002450:Cell Communication; D018858:Germinal Center / Q000502:physiology; D015483:HIV Antibodies / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000502:physiology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000276:immunology*; D008264:Macrophages / Q000821:virology; D020298:U937 Cells; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
D000199:Actins; D019013:CD40 Antigens; D015483:HIV Antibodies; D016655:HIV Core Protein p24; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C514799:p24 protein, Human Immunodeficiency Virus Type 1