Antigenic conservation and immunogenicity of the HIV coreceptor binding site

Abstract

Immunogenic, broadly reactive epitopes of the HIV-1 envelope glycoprotein could serve as important targets of the adaptive humoral immune response in natural infection and, potentially, as components of an acquired immune deficiency syndrome vaccine. However, variability in exposed epitopes and a combination of highly effective envelope-cloaking strategies have made the identification of such epitopes problematic. Here, we show that the chemokine coreceptor binding site of HIV-1 from clade A, B, C, D, F, G, and H and circulating recombinant form (CRF)01, CRF02, and CRF11, elicits high titers of CD4-induced (CD4i) antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 (sCD4). 178 out of 189 (94%) HIV-1–infected patients had CD4i antibodies that neutralized sCD4-pretreated HIV-2 in titers (50% inhibitory concentration) as high as 1:143,000. CD4i monoclonal antibodies elicited by HIV-1 infection also neutralized HIV-2 pretreated with sCD4, and polyclonal antibodies from HIV-1–infected humans competed specifically with such monoclonal antibodies for binding. In vivo, variants of HIV-1 with spontaneously exposed coreceptor binding surfaces were detected in human plasma; these viruses were neutralized directly by CD4i antibodies. Despite remarkable evolutionary diversity among primate lentiviruses, functional constraints on receptor binding create opportunities for broad humoral immune recognition, which in turn serves to constrain the viral quasispecies.

Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers

“…Access of full-size antibodies to CD4i epitopes can be restricted during virus entry into cells (4,16). The crystal structures of two CD4i antibodies, X5 and 17b, in complex with gp120 and sCD4, indicate that access to their epitopes requires long protruding heavy-chain CDR3s (15,17).…”

Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens

“…These epitopes exhibit enhanced exposure as a consequence of gp120 attachment to the cell surface CD4 receptor and are essential for the engagement of entry coreceptors. Because CD4i domains comprise some of the most conserved sequences of the HIV envelope (7,8), cognate antibodies should be highly cross-reactive among viral strains. Moreover, coreceptor binding sequences seem to be immunogenic in humans because HIV-infected persons produce antibodies to CD4i epitopes that can be detected in specific assays (7).…”

“…Because CD4i domains comprise some of the most conserved sequences of the HIV envelope (7,8), cognate antibodies should be highly cross-reactive among viral strains. Moreover, coreceptor binding sequences seem to be immunogenic in humans because HIV-infected persons produce antibodies to CD4i epitopes that can be detected in specific assays (7). In contrast, other conserved/functional envelope domains rarely elicit antibodies in HIV-infected individuals (9,10) or experimental systems and, for a variety of other reasons, may not be practical for vaccine development (9,11).…”

“…To examine anti-CD4i epitope responses in the immunized macaques, day of challenge sera were tested for their ability to block single-chain gp120-CD4 complex interactions with four human anti-CD4i epitope mAbs (17b, 19e, ED47, and X5) known to bind epitopes within or proximal to the coreceptor binding site (7,17,21). Comparative assays were performed with mAb C11, which is directed against a conserved epitope unrelated to the coreceptor binding site, mAb A32, which recognizes a unique CD4i epitope outside the coreceptor binding site (19), and 2G12, which recognizes a neutralizing carbohydrate epitope (29).…”

The good and evil of complement activation in HIV-1 infection

“…34 The HIV-1-specific nAbs described to date interfere with viral attachment to the cellular receptor CD4, binding to the coreceptor (most commonly CCR5 or CXCR4), or postreceptor engagement in the actual fusion process. [35][36][37][38][39][40][41][42][43][44][45] When a host is infected with a virus, Abs are produced against many epitopes on multiple viral proteins. These Abs consist of a mixture of nAbs and non-nAbs, which can contribute to antiviral immunity in four ways: 34 (i) nAbs directly neutralize free virus particles; (ii) both nAbs and non-nAbs trigger complement-mediated lysis of free virus particles and infected cells via specific Ab-antigen binding events and complement activation; (iii) both nAbs and non-nAbs bind to and coat viruses to mediate opsonization and phagocytosis by macrophages and other cells; and (iv) both nAbs and non-nAbs trigger destruction of viruses by stimulating other immune responses such as Ab-dependent cellular cytotoxicity (ADCC).…”