Genome-Wide Association Study on the Development of Cross-Reactive Neutralizing Antibodies in HIV-1 Infected Individuals

Euler, Zelda; Gils, Marit J. van; Boeser‐Nunnink, Brigitte; Schuitemaker, Hanneke; Manen, Daniëlle van

doi:10.1371/journal.pone.0054684

Cited by 21 publications

(24 citation statements)

References 33 publications

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“…Several groups have tested the neutralizing activity in a large group of samples on different virus panels and reported that screening for a reduced panel (6 viruses or less) of selected viruses provided similar information on the presence of cross-reactive neutralizing activity as screening for a large virus panel (30)(31)(32)(33). The broadly neutralizing activity of the patients selected with our 6-virus panel was also confirmed previously with an extended panel, including 25 additional viruses from different subtypes (15).…”

Section: Neutralization Breadth Stability In Bcrn and Control Patientssupporting

confidence: 72%

Evolution of Broadly Cross-Reactive HIV-1-Neutralizing Activity: Therapy-Associated Decline, Positive Association with Detectable Viremia, and Partial Restoration of B-Cell Subpopulations

Ferreira

Merino-Mansilla

Llano

et al. 2013

J Virol

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Little is known about the stability of HIV-1 cross-neutralizing responses. Taking into account the fact that neutralization breadth has been positively associated with plasma viral load, there is no explanation for the presence of broadly neutralizing responses in a group of patients on treatment with undetectable viremia. In addition, the B-cell profile responsible for broadly cross-neutralizing responses is unknown. Here we studied the evolution of neutralizing responses and the B-cell subpopulation distribution in a group of patients with broadly cross-reactive HIV-1-neutralizing activity. We studied neutralization breadth evolution in a group of six previously identified broadly cross-neutralizing patients and six control patients during a 6-year period with a previously described minipanel of recombinant viruses from five different subtypes. B-cell subpopulation distribution during the study was also determined by multiparametric flow cytometry. Broadly cross-neutralizing activity was transient in four broad cross-neutralizers and stable, up to 4.6 years, in the other two. In four out of five broad cross-neutralizers who initiated treatment, a neutralization breadth loss occurred after viremia had been suppressed for as much as 20 months. B-cell subpopulation analyses revealed a significant increase in the frequency of naive B cells in broadly cross-reactive samples, compared with samples with less neutralization breadth (increased from 44% to 62%). We also observed a significant decrease in tissue-like and activated memory B cells (decreased from 19% to 12% and from 17% to 9%, respectively). Our data suggest that HIV-1 broadly cross-neutralizing activity is variable over time and associated with detectable viremia and partial B-cell restoration.

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Section: Neutralization Breadth Stability In Bcrn and Control Patientssupporting

confidence: 72%

Evolution of Broadly Cross-Reactive HIV-1-Neutralizing Activity: Therapy-Associated Decline, Positive Association with Detectable Viremia, and Partial Restoration of B-Cell Subpopulations

Ferreira

Merino-Mansilla

Llano

et al. 2013

J Virol

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“…To this end, various studies have attempted to identify signatures within HIV-1 Env or clinical/host factors that correlate with the development of breadth [10,21,22,31,36,38,69,77,88], on the basis that they could be targeted by immunization strategies. We postulated that factors present as early as several weeks after infection could also be determinants for subsequent development of breadth, as early Env diversity was previously linked with breadth [23].…”

Section: Discussionmentioning

confidence: 99%

Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth

Smith

Burton

Kilembe³

et al. 2016

PLoS Pathog

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A recent study of plasma neutralization breadth in HIV-1 infected individuals at nine International AIDS Vaccine Initiative (IAVI) sites reported that viral load, HLA-A*03 genotype, and subtype C infection were strongly associated with the development of neutralization breadth. Here, we refine the findings of that study by analyzing the impact of the transmitted/founder (T/F) envelope (Env), early Env diversification, and autologous neutralization on the development of plasma neutralization breadth in 21 participants identified during recent infection at two of those sites: Kigali, Rwanda (n = 9) and Lusaka, Zambia (n = 12). Single-genome analysis of full-length T/F Env sequences revealed that all 21 individuals were infected with a highly homogeneous population of viral variants, which were categorized as subtype C (n = 12), A1 (n = 7), or recombinant AC (n = 2). An extensive amino acid sequence-based analysis of variable loop lengths and glycosylation patterns in the T/F Envs revealed that a lower ratio of NXS to NXT-encoded glycan motifs correlated with neutralization breadth. Further analysis comparing amino acid sequence changes, insertions/deletions, and glycan motif alterations between the T/F Env and autologous early Env variants revealed that extensive diversification focused in the V2, V4, and V5 regions of gp120, accompanied by contemporaneous viral escape, significantly favored the development of breadth. These results suggest that more efficient glycosylation of subtype A and C T/F Envs through fewer NXS-encoded glycan sites is more likely to elicit antibodies that can transition from autologous to heterologous neutralizing activity following exposure to gp120 diversification. This initiates an Env-antibody co-evolution cycle that increases neutralization breadth, and is further augmented over time by additional viral and host factors. These findings suggest that understanding how variation in the efficiency of site-specific glycosylation influences neutralizing antibody elicitation and targeting could advance the design of immunogens aimed at inducing antibodies that can transition from autologous to heterologous neutralizing activity.

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“…It is possible that the ability to produce bNAbs is determined by host genetic factors, but there are as yet no studies that support this hypothesis (Euler et al, 2013). An alternative possibility, first suggested by studies in macaques, is that the initial envelope sequence that the immune system encounters is an important determinant of whether or not neutralization breadth develops (Shingai et al, 2012; Walker et al, 2011b).…”

Section: Vaccination To Produce Anti-hiv-1 Neutralizing Antibodiesmentioning

confidence: 99%

Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy

West

Scharf

Scheid

et al. 2014

Cell

316

350

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Despite 30 years of effort, there is no effective vaccine for HIV-1. However, antibodies can prevent HIV-1 infection in humanized mice and macaques when passively transferred. New single-cell-based methods have uncovered many broad and potent donor-derived antibodies, and structural studies have revealed the molecular bases for their activities. The new data suggest why such antibodies are difficult to elicit and inform HIV-1 vaccine development efforts. In addition to protecting against infection, the newly identified antibodies can suppress active infections in mice and macaques, suggesting they could be valuable additions to anti-HIV-1 therapies and to strategies to eradicate HIV-1 infection.

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Genome-Wide Association Study on the Development of Cross-Reactive Neutralizing Antibodies in HIV-1 Infected Individuals

Cited by 21 publications

References 33 publications

Evolution of Broadly Cross-Reactive HIV-1-Neutralizing Activity: Therapy-Associated Decline, Positive Association with Detectable Viremia, and Partial Restoration of B-Cell Subpopulations

Evolution of Broadly Cross-Reactive HIV-1-Neutralizing Activity: Therapy-Associated Decline, Positive Association with Detectable Viremia, and Partial Restoration of B-Cell Subpopulations

Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth

Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy

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