Randomized, Double‐Blind, Placebo‐Controlled Efficacy Trial of a Bivalent Recombinant Glycoprotein 120 HIV‐1 Vaccine among Injection Drug Users in Bangkok, Thailand

Pitisuttithum, Punnee; Gilbert, Peter B.; Gurwith, Marc; Heyward, William L.; Martin, Michael; Griensven, Fritz van; Hu, Dale J.; Tappero, Jordan W.

doi:10.1086/508748

Cited by 749 publications

(654 citation statements)

References 37 publications

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“…Indeed, we found that gp120 sulfation in certain continuous cell lines is inefficient, presumably because of limited endogenous expression of tyrosyl sulfotransferases. This observation has important practical implications, because cell lines such as CHO and HEK293 are widely used for the production of recombinant gp120 for structural, biological, and clinical studies, including atomic-level structure determination (6-10, 18), standardized neutralization assays (46), and experimental vaccine trials (47,48). These considerations emphasize the need to use in vitro expression systems that implement physiologically relevant posttranslational modifications.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2–V3 interaction and modulates neutralization sensitivity

Cimbro¹,

Gallant²,

Dolan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Elicitation of broadly neutralizing antibodies is essential for the development of a protective vaccine against HIV-1. However, the native HIV-1 envelope adopts a protected conformation that conceals highly conserved sites of vulnerability from antibody recognition. Although high-definition structures of the monomeric core of the envelope glycoprotein subunit gp120 and, more recently, of a stabilized soluble gp140 trimer have been solved, fundamental aspects related to the conformation and function of the native envelope remain unresolved. Here, we show that the conserved central region of the second variable loop (V2) of gp120 contains sulfated tyrosines (Tys173 and Tys177) that in the CD4-unbound prefusion state mediate intramolecular interaction between V2 and the conserved base of the third variable loop (V3), functionally mimicking sulfated tyrosines in CCR5 and anti-coreceptor-binding-site antibodies such as 412d. Recombinant gp120 expressed in continuous cell lines displays low constitutive levels of V2 tyrosine sulfation, which can be enhanced markedly by overexpression of the tyrosyl sulfotransferase TPST2. In contrast, virion-associated gp120 produced by primary CD4 + T cells is inherently highly sulfated. Consistent with a functional role of the V2 sulfotyrosines, enhancement of tyrosine sulfation decreased binding and neutralization of HIV-1 BaL by monomeric soluble CD4, 412d, and anti-V3 antibodies and increased recognition by the trimer-preferring antibodies PG9, PG16, CH01, and PGT145. Conversely, inhibition of tyrosine sulfation increased sensitivity to soluble CD4, 412d, and anti-V3 antibodies and diminished recognition by trimer-preferring antibodies. These results identify the sulfotyrosine-mediated V2-V3 interaction as a critical constraint that stabilizes the native HIV-1 envelope trimer and modulates its sensitivity to neutralization.T he development of a protective vaccine remains a high priority for the global control of the HIV/AIDS epidemic (1). However, the unique biological features of HIV-1 make this task extremely challenging. The main obstacles include the ability of the virus to integrate into the host chromosomes, a remarkable degree of genetic variability, and the cryptic, antibody-shielded conformation adopted by the viral envelope in the native spikes that protrude from the virion surface (2). These spikes are composed of homotrimers of heterodimers of the envelope glycoprotein subunits gp120 and gp41 maintained in an energetically unfavorable, metastable conformation (3, 4). Upon binding to CD4 and a coreceptor such as CCR5 or CXCR4, gp120 undergoes dramatic conformational changes that lead to a low-energy state, creating permissive conditions for activation of the gp41 fusogenic mechanism (3). In the prefusion conformation, gp120 effectively conceals its highly conserved receptor-and coreceptor-binding sites from antibody recognition, imposing a high-entropy penalty for interaction with CD4 or antibodies to the coreceptor-binding site such as 17b; in contrast, in the open, l...

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Section: Discussionmentioning

confidence: 99%

Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2–V3 interaction and modulates neutralization sensitivity

Cimbro¹,

Gallant²,

Dolan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…(C) Subunit rotation along designated subunit axes (S 1 , S 2 , and S 3 , as previously described, protruding out of the plane of the page) further weakens gp120/gp41 interface, likely freeing up gp41 N-helix for association with the C-helix. ment of gp140 in a metastable state and the putative locations of its exposed epitopes contribute to the characterization of subsequent events occurring prior to membrane fusion, and utilization of gp140 as an immunogen in the unliganded and liganded forms with knowledge of epitope location and exposure could prove useful in elicitation of antibodies against both conserved epitopes, as opposed to the use of monomeric gp120 or of adenovirus-based cell-mediated immunity, thus providing a feasible direction for rational immunogen design (12,(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

Moscoso

Sun²,

Poon

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The human immunodeficiency virus envelope protein is the key element mediating entry into host cells. Conformational rearrangement of Env upon binding to the host CD4 receptor and chemokine coreceptor drives membrane fusion. We elucidated the quaternary arrangement of the soluble Env trimeric immunogen o-gp140ΔV2TV1, in both its native (unliganded) and CD4-induced (liganded) states by cryoelectron microscopy and molecular modeling. The liganded conformation was elicited by binding gp140 to the synthetic CD4-mimicking miniprotein CD4m. Upon CD4m binding, an outward domain shift of the three gp120 subunits diminishes gp120-gp41 interactions, whereas a "flat open" concave trimer apex is observed consequent to gp120 tilting away from threefold axis, likely juxtaposing the fusion peptide with the host membrane. Additional features observed in the liganded conformation include rotations of individual gp120 subunits that may release gp41 for N-and C-helix refolding and also may lead to optimal exposure of the elicited coreceptor binding site. Such quaternary arrangements of gp140 lead to the metastable liganded conformation, with putative locations of exposed epitopes contributing to a description of sequential events occurring prior to membrane fusion. Our observations imply a mechanism whereby a soluble Env trimeric construct, as opposed to trimers extracted from virions, may better expose crucial epitopes such as the CD4 binding site and V3, as well as epitopes in the vicinity of gp41, subsequent to conjugation with CD4m. Structural features gleaned from our studies should aid the design of Env-based immunogens for inducement of potent broadly neutralizing antibodies against exposed conformational epitopes.T he human immunodeficiency virus envelope proteins gp120 and gp41 associate in a trimeric arrangement (1-3) and mediate membrane fusion through conformational rearrangement and fusion peptide insertion into the host membrane. The gp120 tertiary conformational change observed via X-ray crystallography has not been definitively characterized in the context of a quaternary structure. Several observations have been gleaned from tomography studies, though with inconclusive and sometimes contradictory results. Quaternary structural features reported previously include trimer morphology, with some groups reporting a mushroom-like shape and others a more rod-like arrangement, as well as the relative location of the primary epitope, hypervariable loops, and N-and C-termini, which have some variation among the different tomograms. Another point of conflict is the presence of a cavity at the threefold axis, capped by a density. One final feature is the arrangement of gp41, with some groups reporting a thin, stalk-like rod arrangement of gp41 and another group reporting a more splayed out, tripod-like conformation of gp41 proximal to the viral membrane. Taken together, these contrasting features portray a heterogeneous set of registers that seem to hinder a cohesive and thorough model of ligand-induced quaternary arrangement...

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“…Education, identification and treatment of infected persons with antiretroviral drugs, male circumcision, condoms, and needle exchange programs have been effective at curtailing the epidemic, but declines in the rate of new infections have plateaued, and it appears unlikely that the goal of <500 000 new adult infections per year will be achieved by 2020. An effective HIV‐1 vaccine could contribute to further reductions of infections as part of a coordinated prevention strategy,2 but to date, testing of candidate vaccines in efficacy trials has been disappointing 3, 4, 5, 6, 7 with only one trial showing any degree of vaccine efficacy 8…”

Section: Introductionmentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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Randomized, Double‐Blind, Placebo‐Controlled Efficacy Trial of a Bivalent Recombinant Glycoprotein 120 HIV‐1 Vaccine among Injection Drug Users in Bangkok, Thailand

Abstract: Despite the successful completion of this efficacy trial, the vaccine did not prevent HIV-1 infection or delay HIV-1 disease progression.

Cited by 749 publications

References 37 publications

Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2–V3 interaction and modulates neutralization sensitivity

Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2–V3 interaction and modulates neutralization sensitivity

Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

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