Abstract
HIV-1-infected individuals raise a polyclonal antibody response targeting multiple envelope glycoprotein (Env) epitopes. Interestingly, two classes of non-neutralizing CD4-induced (CD4i) antibodies, present in the majority of HIV-1-infected individuals have been described to mediate antibody-dependent cellular cytotoxicity (ADCC) in the presence of small CD4 mimetic compounds (CD4mc). These antibodies recognize the coreceptor binding site (CoRBS) and the constant region one and two (C1C2 or inner domain cluster A) of the gp120. In combination with CD4mc they have been shown to stabilize an antibody-vulnerable Env conformation, known as State 2A. Here we evaluated the importance of these two families of Abs in ADCC responses by immunizing guinea pigs with gp120 immunogens that have been modified to elicit or not these types of antibodies. Underlying the importance of anti-CoRBS and anti-cluster A Abs in stabilizing State 2A, ADCC responses were only observed in the presence of these two types of CD4i antibodies. Altogether, our results suggest that these two families of CD4i antibodies must be taken into account when considering future strategies relying on the use of CD4mc to eliminate HIV-1-infected cells in vivo.
Highlights
The envelope glycoproteins (Env) of the human immunodeficiency virus type 1 (HIV-1) mediate viral fusion and are assembled into a trimer of heterodimers composed of the transmembrane gp41 and exterior gp120 subunits [1,2]
The only anti-HIV-1 vaccine trial that presented a modest level of protection (31.2%), the RV144 trial [6], elicited non-neutralizing antibodies
Antibody-dependent cellular cytotoxicity (ADCC) was not identified as a correlate of protection in the RV144 trial, a non-significant trend towards a lower risk of HIV-1 infection was observed among vaccine recipients with higher antibody-dependent cellular cytotoxicity (ADCC) responses and low IgA responses [9]
Summary
The envelope glycoproteins (Env) of the human immunodeficiency virus type 1 (HIV-1) mediate viral fusion and are assembled into a trimer of heterodimers composed of the transmembrane gp and exterior gp120 subunits [1,2]. CD4 binding “opens” Env by reorganizing the V1V2 and V3 loops resulting in the adoption of the CD4-bound conformation, referred as state 3 [16,17,18] This conformation is vulnerable to ADCC mediated by CD4-induced (CD4i) antibodies elicited by vaccination or present in the sera from most HIV-1-infected individuals [19,20,21,22]. A promising approach to achieve this is the use of small molecule CD4 mimetics (CD4mc) which binds into the gp120 Phe cavity and induce conformational changes resulting in the exposure of several CD4i epitopes [23,24,25,26] This strategy was recently used to prove that CD4mc can synergize with antibodies elicited by monomeric gp120 to protect non-human primates (NHPs) from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV) [21]. Our results stress the importance of eliciting both type of antibodies that in combination with CD4mc are able to effectively eliminate HIV-1-infected cells by ADCC
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