Cross‐Reactive Neutralizing Humoral Immunity Does Not Protect from HIV Type 1 Disease Progression

Euler, Zelda; Gils, Marit J. van; Bunnik, Evelien M.; Phung, Pham; Schweighardt, Becky; Wrin, Terri; Schuitemaker, Hanneke

doi:10.1086/651144

Cited by 143 publications

(199 citation statements)

References 46 publications

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“…However, R166, D167, and K168 are very well conserved across subtypes A, B, and C. The existence of subtype-specific epitopes is borne out by existing MAbs-2G12 and 2F5 fail to neutralize most subtype C viruses because of genetic variability in the epitope, and IgG1b12 neutralizes two-thirds of subtype B and C viruses but only a third of subtype A viruses (2). Preferential neutralization by polyclonal plasma of subtype-matched heterologous viruses has also been shown by us (32) and others (1,3,8,38,41). Indeed, within the CAPRISA cohort, all of whose members were infected with subtype C viruses, we note significantly better neutralization of subtype C than of subtype B viruses (data not shown).…”

Section: Discussionmentioning

confidence: 80%

Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

Moore

Gray

Sheward

et al. 2011

J Virol

149

155

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The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers.

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Section: Discussionmentioning

confidence: 80%

Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

Moore

Gray

Sheward

et al. 2011

J Virol

149

155

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“…The development of neutralization breadth does not appear to impact the progression of HIV‐1 disease48, 67; for example, many individuals in these longitudinal cohorts went on antiretroviral therapy as part of standard of care during the course of study,48, 50 including those with high degrees of breadth 48. Examination of viruses and antibodies taken from the same HIV‐1‐infected individuals has consistently shown that circulating bnAbs cause extinction of susceptible virus populations despite ongoing viremia,23, 24, 25 although viruses susceptible to less potent neutralizing antibodies continue to circulate 25.…”

Section: Development Of Broadly Neutralizing Antibodies In Hiv‐1 Infementioning

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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“…However, because some HIV-1-infected individuals can develop bnAbs over the course of infection, these various evasion strategies are not insurmountable (1,(25)(26)(27). Although bnAbs do not seem to confer significant protection against disease progression in infected individuals (28,29), their induction through vaccination might prevent the acquisition of infection. Thus, the epitopes recognized by bnAbs are now being carefully scrutinized to serve as templates for rational vaccine design.…”

mentioning

confidence: 99%

Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9

Julien

Lee

Cupo

et al. 2013

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

232

303

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PG9 is the founder member of an expanding family of glycandependent human antibodies that preferentially bind the HIV (HIV-1) envelope (Env) glycoprotein (gp) trimer and broadly neutralize the virus. Here, we show that a soluble SOSIP.664 gp140 trimer constructed from the Clade A BG505 sequence binds PG9 with high affinity (∼11 nM), enabling structural and biophysical characterizations of the PG9:Env trimer complex. The BG505 SOSIP.664 gp140 trimer is remarkably stable as assessed by electron microscopy (EM) and differential scanning calorimetry. EM, small angle X-ray scattering, size exclusion chromatography with inline multiangle light scattering and isothermal titration calorimetry all indicate that only a single PG9 fragment antigen-binding (Fab) binds to the Env trimer. An ∼18 Å EM reconstruction demonstrates that PG9 recognizes the trimer asymmetrically at its apex via contact with two of the three gp120 protomers, possibly contributing to its reported preference for a quaternary epitope. Molecular modeling and isothermal titration calorimetry binding experiments with an engineered PG9 mutant suggest that, in addition to the N156 and N160 glycan interactions observed in crystal structures of PG9 with a scaffolded V1/V2 domain, PG9 makes secondary interactions with an N160 glycan from an adjacent gp120 protomer in the antibody-trimer complex. Together, these structural and biophysical findings should facilitate the design of HIV-1 immunogens that possess all elements of the quaternary PG9 epitope required to induce broadly neutralizing antibodies against this region. R ational immunogen design is an increasingly promising approach for development of an effective human immunodeficiency virus-1 (HIV-1) vaccine. The recent discovery of many new and potent broadly neutralizing antibodies (bnAbs) has helped define conserved sites of vulnerability on the HIV-1 envelope (Env) glycoprotein (gp) complex that mediates viral entry into cells (refs. 1-6 and reviewed in refs. 7-11). Passive immunization studies show that sterilizing immunity can be achieved if sufficient amounts of bnAbs are present before virus challenge in macaques (12-16). Hence, intensive efforts are ongoing to design immunogens capable of re-eliciting these types of bnAbs by vaccination.The major difficulty in mounting an effective antibody response against HIV-1 resides in the multiple evasion strategies that have evolved in Env. An error-prone reverse transcriptase drives a high degree of Env sequence diversity (17-19). The few conserved regions of Env are shielded by an extensive array of glycans (20-24) and are often occluded by more variable structures, such as the V1-V5 loops. However, because some HIV-1-infected individuals can develop bnAbs over the course of infection, these various evasion strategies are not insurmountable (1,(25)(26)(27). Although bnAbs do not seem to confer significant protection against disease progression in infected individuals (28, 29), their induction through vaccination might prevent the acquisition of infection. ...

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Cross‐Reactive Neutralizing Humoral Immunity Does Not Protect from HIV Type 1 Disease Progression

Cited by 143 publications

References 46 publications

Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

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

Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9

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