Natural mucosal antibodies reactive with first extracellular loop of CCR5 inhibit HIV-1 transport across human epithelial cells

Abstract

Anti-CCR5 Abs shed light on the immunological mechanisms involved in the control of HIV-1 infection in a model that can be considered an experimentum naturae for resistance to HIV. They could be useful in the design of new strategies against HIV infection at mucosal sites.

ERK1-Based Pathway as a New Selective Mechanism To Modulate CCR5 with Natural Antibodies

“…Indeed, at a mucosal site, the role of CCR5 seems to be different from that observed in CD4 + T lymphocytes, as HIV binds CCR5 intracellularly in the endosome (41,42) and HIV transcytosis inhibition with anti-CCR5 Ab pos performed in epithelial cells requires 1 h of Ab incubation to block HIV infection and not 48 h, as for T lymphocytes (22); thus we hypothesize that at a mucosal site, CCR5 Ab pos bind the receptor and reach the CCR5 intracellularly, thereby precluding interaction with HIV and then transcytosis (22), rather than inducing long-lasting internalization. In this work we used RANTES/CCL4 ligand as a control of the common internalization pathway of CCR5 previously described in T cells (26,43,44).…”

“…Previous works published by our and other groups (15)(16)(17)(18) proved the existence of anti-CCR5 Abs, which induced long-lasting internalization of CCR5 in the sera of a subset of LTNP and HIV-exposed uninfected subjects (12,(18)(19)(20)(21)(22). The mechanisms underlying this unconventional and atypical long-lasting downregulation of CCR5 required further investigation.…”

HIV infection and the gastrointestinal immune system

“…73 In addition, antibodies directed against host CCR5 have been observed in highly exposed uninfected individuals and in infected individuals classified as long-term nonprogressors; these antibodies have inhibited HIV transport across human epithelial cells in vitro. 74,75 It remains clear, however, that the majority of chronically HIV-infected individuals do not mount vigorous HIV-specific IgA antibody responses either locally in mucosal sites or systemically. 76 Thus, these findings suggest that induction of a functional HIV-specific immune response would help to control viral replication and might even inhibit it.…”

HIV Envelope-Specific Antibody and Vaccine Efficacy

“…Cell-free virus transcytosis is also possible but inefficient (Bobardt et al, 2007;Bomsel, 1997). Rather than fusion and infection, interactions between viral components, including gp41 (Alfsen et al, 2001), gp120 (Bobardt et al, 2007), and gp160 (Hocini et al, 1997), and host epithelial cell surface molecules, such as glycosphingolipid galactosyl-ceramide (GalCer) (Alfsen & Bomsel, 2002;Meng et al, 2002), an important component of endocytotic "raft" membrane microdomains, the coreceptor CCR5 (Bomsel et al, 2007), and the heparin sulfate proteoglycan attachment receptor, agrin (Alfsen et al, 2005), lead to transcytosis of the virus across the epithelial barrier and its trapping by submucosal dendritic cells which disseminate it to target CD4 + T cells. Immunoglobulin A (IgA) and immunoglobulin G (IgG) anti-HIV antibodies have been detected in nearly all external secretions.…”