Premium
Long‐Distance Tunneling Nanotubules Shuttle Immunoglobulin Class Switch‐Suppressing Factors from HIV‐Infected Macrophages to B Cells
Author(s) -
Xu Weifeng,
Santini Paul A,
Shan Meimei,
Chen Kang,
Ball Susan C,
Chiu April,
Kingsley Lawrence A,
Rinaldo Charles R,
Chadburn Amy,
Knowles Daniel M,
He Bing,
Cerutti Andrea
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.856.26
Subject(s) - immunoglobulin class switching , cytidine deaminase , cd40 , microbiology and biotechnology , biology , transfection , antibody , somatic hypermutation , immune system , b cell , virology , immunology , in vitro , cell culture , cytotoxic t cell , biochemistry , genetics
Class switching from IgM to IgG and IgA is essential for systemic and mucosal immune responses against viruses and requires activation of follicular B cells by CD4 + T cells through CD40‐CD40L interaction. The mechanism by which HIV evades virus‐specific IgG and IgA responses remains unclear. We found that lymphoid follicles from HIV‐infected patients contained Nef, an early viral protein involved in AIDS development. In these follicles, long‐distance membrane tethers shuttled Nef from HIV‐infected macrophages to B cells. This process was associated with decreased signaling of CD40 via NF‐κB and with loss of activation‐induced cytidine deaminase (AID), a CD40‐inducible enzyme essential for class switching. In vitro studies showed that macrophages productively infected by HIV or transfected with a Nef‐GFP‐expressing construct were capable of translocating Nef to B cells via actin‐propelled and ATP‐dependent membrane channels, including long‐range tunneling nanotubules. Transfer of Nef to B cells required a clathrin‐dependent pathway that involved the guanine nucleotide exchange factor Vav as well as downstream Rho, Rac and Cdc42 small GTPases. Once in B cells, Nef inhibited CD40L‐induced AID expression and subsequent IgG and IgA class switching. These studies indicate that HIV hijacks a physiological intercellular connectivity network to generate B cell‐intrinsic defects and evade humoral immunity.