title: Cross-Reactive Human IgM-Derived Monoclonal Antibodies that Bind to HIV-1 Envelope Glycoproteins.
abstract: Elicitation of antibodies with potent and broad neutralizing activity against HIV by immunization remains a challenge. Several monoclonal antibodies (mAbs) isolated from humans with HIV-1 infection exhibit such activity but vaccine immunogens based on structures containing their epitopes have not been successful for their elicitation. All known broadly neutralizing mAbs (bnmAbs) are immunoglobulin (Ig) Gs (IgGs) and highly somatically hypermutated which could impede their elicitation. Ig Ms (IgMs) are on average significantly less divergent from germline antibodies and are relevant for the development of vaccine immunogens but are underexplored compared to IgGs. Here we describe the identification and characterization of several human IgM-derived mAbs against HIV-1 which were selected from a large phage-displayed naive human antibody library constructed from blood, lymph nodes and spleens of 59 healthy donors. These antibodies bound with high affinity to recombinant envelope glycoproteins (gp140s, Envs) of HIV-1 isolates from different clades. They enhanced or did not neutralize infection by some of the HIV-1 primary isolates using CCR5 as a coreceptor but neutralized all CXCR4 isolates tested although weakly. One of these antibodies with relatively low degree of somatic hypermutation was more extensively characterized. It bound to a highly conserved region partially overlapping with the coreceptor binding site and close to but not overlapping with the CD4 binding site. These results suggest the existence of conserved structures that could direct the immune response to non-neutralizing or even enhancing antibodies which may represent a strategy used by the virus to escape neutralizing immune responses. Further studies will show whether such a strategy plays a role in HIV infection of humans, how important that role could be, and what the mechanisms of infection enhancement are. The newly identified mAbs could be used as reagents to further characterize conserved non-neutralizing, weakly neutralizing or enhancing epitopes and modify or remove them from candidate vaccine immunogens.
authors.affiliation: Protein Interactions Group, Center for Cancer Research Nanobiology Program, National Cancer Institute (NCI)-Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Huaxin
authors.initials: H
authors.lastname: Liao
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Quinnan
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Broder
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov