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Publication Abstract from PubMed

The RV144 vaccine trial implicated epitopes in the C1 region of gp120 (A32-like epitopes) as targets of potentially protective antibody-dependent cellular cytotoxicity (ADCC) responses. A32-like epitopes are highly immunogenic as infected or vaccinated individuals frequently elicit antibodies specific for these determinants. Antibody-binding titers as measured by ELISA against these epitopes, however, do not consistently correlate with protection. Here, we report crystal structures of CD4-stabilized gp120 cores complexed with the Fab fragments of two non-neutralizing, A32-like monoclonal antibodies (mAbs), named N5-i5 and 2.2c, that compete for antigen binding and exhibit similar binding affinities, yet mediate a 75-fold difference in ADCC potency. We find that these mAbs recognize overlapping epitopes formed by mobile layers 1 and 2 of the gp120 inner domain including the C1-C2 regions, but bind gp120 at different angles via juxtaposed VH and VL contact surfaces. A comparison of structural and immunological data further showed that antibody orientation on bound antigen and the capacity to form multivalent antigen-antibody complexes on target cells were key determinants for ADCC potency, with the latter process having the greater impact. These studies provide atomic level definition of A32-like epitopes implicated as targets of protective antibodies in RV144. Moreover, these studies establish that epitope structure and mode of antibody binding can dramatically affect the potency of Fc-mediated effector function against HIV-1. These results provide key insights for understanding, refining, and improving the outcome of HIV-vaccine trials, in which relevant immune responses are facilitated by A32-like elicited responses. IMPORTANCE: HIV-1 Env is a primary target for antibodies elicited during infection. Although a small number of infected individuals elicit broadly neutralizing antibodies, the bulk of humoral response consists of antibodies that do not neutralize or do so with limited breadth but may effect protection through Fc receptor-dependent processes, such as antibody-dependent cellular cytotoxicity (ADCC). Understanding these non-neutralizing responses is an important aspect in elucidating the complete spectrum of immune response against HIV-1 infection. With this report we provide the first atomic level definition of non-neutralizing CD4-induced epitopes in the N-terminal region of the HIV-1 gp120 (A32-like epitopes). Further, our studies point toward the dominant role of precise epitope targeting and mode of antibody attachment in ADCC responses even when largely overlapping epitopes are involved. Such information provides key insights into the mechanisms of Fc-mediated antibody function to HIV-1 and helps understand the outcome of vaccine trials based on humoral immunity.

Structural Definition of an Antibody-Dependent Cellular Cytotoxicity (ADCC) Response Implicated in Reduced Risk for HIV-1 Infection.,Acharya P, Tolbert WD, Gohain N, Wu X, Yu L, Liu T, Huang W, Huang CC, Do Kwon Y, Louder RK, Luongo TS, McLellan JS, Pancera M, Yang Y, Zhang B, Flinko R, Foulke JS Jr, Sajadi MM, Kamin-Lewis R, Robinson JE, Martin L, Kwong PD, Guan Y, DeVico AL, Lewis GK, Pazgier M J Virol. 2014 Aug 27. pii: JVI.02194-14. PMID:25165110^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.