HIV Antibody Fc N-Linked Glycosylation Is Associated with Viral Rebound

Offersen, Rasmus; Yu, Wen Han; Scully, Eileen P.; Jülg, Boris; Euler, Zelda; Sadanand, Saheli; Garcia-Dominguez, Dario; Li, Zheng; Rasmussen, Thomas A; Jennewein, Madeleine F.; Linde, Caitlyn; Sassic, Jessica K.; Lofano, Giuseppe; Viganó, Selena; Stephenson, Kathryn E.; Fischinger, Stephanie; Suscovich, Todd J.; Lichterfeld, Mathias; Lauffenburger, Douglas A.; Rosenberg, Erik S.; Allen, Todd M.; Altfeld, Marcus; Charles, Richelle C.; Østergaard, Lars; Tolstrup, Martin; Barouch, Dan H.; Søgaard, Ole Schmeltz; Alter, Galit

doi:10.1016/j.celrep.2020.108502

Cited by 19 publications

(20 citation statements)

References 50 publications

(56 reference statements)

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“…We performed both “common” variant (polymorphisms observed at minor allele frequency, MAF, ≧5%) and rare-variant, gene-based analyses. Overall, our findings support prior data suggesting an important role for type I interferon signaling [28], the “transcriptionally active” HIV reservoir [29–32], and glycosylation [33–35]) in the maintenance of the HIV reservoir. In addition, our findings link previously reported genetic associations with viral control during untreated HIV disease (e.g., with MHC class I alleles [13, 20] and CCR5 Δ 32 [23, 24, 36]), now with the HIV reservoir during treated disease, and highlight additional novel pathways that warrant further study in downstream functional studies.…”

Section: Introductionsupporting

confidence: 90%

“…HIV total DNA was associated with “N-Glycan Processing” (normalized enrichment score, NES=1.76, q=0.13), consistent with recent emerging data of the critical role of glycosylation in HIV persistence. Indeed, glycomic biomarkers were shown to predict time-to-viral rebound during treatment interruption, a clinical measure of the size of the HIV reservoir in previously ART-suppressed HIV-infected individuals, in at least 2 studies [35, 63]. A recent study suggests that changes in IFN-α signaling may induce glycomic alterations that then modulate the host immune response (e.g., CD8+ T and NK cell responses) [33].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

Siegel

Thanh

Wan

et al. 2021

Preprint

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BackgroundPrior host genomewide association studies have failed to observe an association with the HIV reservoir.MethodsCustom whole exome sequencing and direct HLA typing were performed from 202 HIV+ ART-suppressed individuals and associated with 4 measures of the circulating CD4+ T cell reservoir: total DNA, unspliced (us)RNA, RNA/DNA, and intact DNA. Common variant, gene-based, and HLA analyses were performed using linear mixed models adjusted for sex, timing of ART initiation, nadir CD4 count, input cell count, and ancestry.ResultsHIV total DNA was associated with variants in genes involved in type I interferon (MX1, PPP1CB, DDX3X) and MHC class I peptide recognition (LRMP), while HIV usRNA was associated with a variant related to lymphocyte lymph node migration (PLVAP; this SNP was also <30kb from BST2, which encodes tetherin, an HIV host restriction factor). Gene-based analyses demonstrated significant associations with type I interferon (intact DNA), glycosylation (total DNA), and retroviral transcription (usRNA). HLA “protective” B*57:01 and “risk” C*07 alleles, as well as CCR5Δ32. were associated with HIV usRNA and total DNA, but not intact DNA.ConclusionsHost genetic variation in type I interferon, MHC class I, glycosylation, residual viral transcription, and lymphocyte lymph node migration may influence the circulating HIV CD4+ T cell reservoir.

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Section: Introductionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

Siegel

Thanh

Wan

et al. 2021

Preprint

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“…Two recent studies identified plasma and antibody glycomic biomarkers, in particular digalactosylated G2 glycans on IgG, as predictive markers of post-treatment remission (Giron et al, 2020;Offersen et al, 2020). Moreover, pre-ATI levels of HIV gp120-specific G2 glycans inversely correlated with CA HIV unspliced RNA levels (Offersen et al, 2020), providing a possible explanation why it was predictive of longer time to rebound. Although the role of cytotoxic T lymphocytes (CTLs) in post-treatment HIV remission is probably not as pronounced as in spontaneous ("elite") HIV control and post-treatment controllers mostly lack protective HLA alleles (Goujard et al, 2012;Sáez-Cirión et al, 2013;Maenza et al, 2015), this does not mean that other components of the host immunity are not important.…”

Section: Predicting Post-treatment Hiv Remission: Time For a Comprehementioning

confidence: 99%

“…Pre-ART levels of T-cell exhaustion markers (PD-1, Tim-3, and Lag-3) have been shown to predict the time to viral rebound, although their on-ART levels were not predictive (Hurst et al, 2015). Two recent studies identified plasma and antibody glycomic biomarkers, in particular digalactosylated G2 glycans on IgG, as predictive markers of post-treatment remission (Giron et al, 2020;Offersen et al, 2020). Moreover, pre-ATI levels of HIV gp120-specific G2 glycans inversely correlated with CA HIV unspliced RNA levels (Offersen et al, 2020), providing a possible explanation why it was predictive of longer time to rebound.…”

Section: Predicting Post-treatment Hiv Remission: Time For a Comprehementioning

confidence: 99%

Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?

Pasternak

Psomas²,

Berkhout

2021

Front. Microbiol.

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Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function. However, due to the persistence of long-lived HIV reservoirs, therapy interruption almost inevitably leads to a fast viral rebound. A small percentage of individuals who are able to control HIV replication for extended periods after therapy interruption are of particular interest because they may represent a model of long-term HIV remission without ART. These individuals are characterized by a limited viral reservoir and low reservoir measures can predict post-treatment HIV remission. However, most individuals with a low reservoir still experience fast viral rebound. In this Perspective, we discuss the possible reasons behind this and propose to develop an integral profile, composed of viral and host biomarkers, that could allow the accurate prediction of post-treatment HIV remission. We also propose to incorporate information on the chromatin context of the proviral integration sites into the characterization of the HIV reservoir, as this likely influences the reactivation capacity of latent proviruses and, together with the actual number of intact proviruses, contributes to the replication competence of the reservoir.

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“…Time to viral rebound remains the best and clinically most relevant indicator of intervention efficacy. Interestingly, Offersen et al (68) were able to show that HIV-1 specific antibody Fc Ngalactosylation (glycosylation) is associated with viral rebound after ATI across three independent HIV cohorts. The mechanistical involvement of these glycosylated gp120 Env specific antibodies in viral control remains unclear and only antibody-dependent neutrophil phagocytosis (ADNP) and ADCD were linked to rebound time in this study.…”

Section: Modified Bnabs In Hiv-1 Curementioning

confidence: 99%

TLR-Agonist Mediated Enhancement of Antibody-Dependent Effector Functions as Strategy For an HIV-1 Cure

Hvilsom

Søgaard

2021

Front. Immunol.

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BackgroundThe current treatment for HIV-1 is based on blocking various stages in the viral replication cycle using combination antiretroviral therapy (ART). Even though ART effectively controls the infection, it is not curative, and patients must therefore continue treatment life-long.AimHere we review recent literature investigating the single or combined effect of toll-like receptor (TLR) agonists and broadly neutralizing antibodies (bNAbs) with the objective to evaluate the evidence for this combination as a means towards an HIV-1 cure.ResultsMultiple preclinical studies found significantly enhanced killing of HIV-1 infected cells by TLR agonist-induced innate immune activation or by Fc-mediated effector functions following bNAb administration. However, monotherapy with either agent did not lead to sustained HIV-1 remission in clinical trials among individuals on long-term ART. Notably, findings in non-human primates suggest that a combination of TLR agonists and bNAbs may be able to induce long-term remission after ART cessation and this approach is currently being further investigated in clinical trials.ConclusionPreclinical findings show beneficial effects of either TLR agonist or bNAb administration for enhancing the elimination of HIV-1 infected cells. Further, TLR agonist-mediated stimulation of innate effector functions in combination with bNAbs may enhance antibody-dependent cellular cytotoxicity and non-human primate studies have shown promising results for this combination strategy. Factors such as immune exhaustion, proviral bNAb sensitivity and time of intervention might impact the clinical success.

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HIV Antibody Fc N-Linked Glycosylation Is Associated with Viral Rebound

Cited by 19 publications

References 50 publications

Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?

TLR-Agonist Mediated Enhancement of Antibody-Dependent Effector Functions as Strategy For an HIV-1 Cure

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