Preferential Presentation of High-Affinity Immune Complexes in Germinal Centers Can Explain How Passive Immunization Improves the Humoral Response

Garg, Amar K.; Desikan, Rajat; Dixit, Narendra M.

doi:10.1016/j.celrep.2019.11.030

Cited by 38 publications

(78 citation statements)

References 78 publications

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“…Following the observation of Nishimura et al [10] that there was no significant generation of anti-gp120 Abs in controllers, we ignored the ability of bNAbs to upregulate the humoral response [52,53]. Our study is thus conservative in its assessment of the influence of bNAbs.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

2020

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Antiretroviral therapy (ART) for HIV-1 infection is lifelong. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit longterm control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy.

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Section: Plos Computational Biologymentioning

confidence: 99%

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

2020

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“…bNAbs are known to engage the immune system via multiple mechanisms [20,87,[89][90][91]. The result could be heightened activation, which for HIV-1 infection, could mean greater susceptibility of target CD4 T cells.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection

Saha

Dixit

2020

PLoS Comput Biol

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Passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 appears a promising strategy for eliciting long-term HIV-1 remission. When administered concomitantly with the cessation of antiretroviral therapy (ART) to patients with established viremic control, bNAb therapy is expected to prolong remission. Surprisingly, in clinical trials on chronic HIV-1 patients, the bNAb VRC01 failed to prolong remission substantially. Identifying the cause of this failure is important for improving VRC01-based therapies and unraveling potential vulnerabilities of other bNAbs. In the trials, viremia resurged rapidly in most patients despite suppressive VRC01 concentrations in circulation, suggesting that VRC01 resistance was the likely cause of failure. ART swiftly halts viral replication, precluding the development of resistance during ART. If resistance were to emerge post ART, virological breakthrough would have taken longer than without VRC01 therapy. We hypothesized therefore that VRC01-resistant strains must have been formed before ART initiation, survived ART in latently infected cells, and been activated during VRC01 therapy, causing treatment failure. Current assays preclude testing this hypothesis experimentally. We developed a mathematical model based on the hypothesis and challenged it with available clinical data. The model integrated within-host HIV-1 evolution, stochastic latency reactivation, and viral dynamics with multiple-dose VRC01 pharmacokinetics. The model predicted that single but not higher VRC01-resistant mutants would pre-exist in the latent reservoir. We constructed a virtual patient population that parsimoniously recapitulated inter-patient variations. Model predictions with this population quantitatively captured data of VRC01 failure from clinical trials, presenting strong evidence supporting the hypothesis. We attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly when VRC01 was at trough levels. Pre-existing resistant proviruses in the latent reservoir may similarly compromise other bNAbs. Our study provides a framework for designing bNAb-based therapeutic protocols that would avert such failure and maximize HIV-1 remission.

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“…Furthermore, the blunting effect noted has not been comprehensively defined, with a gap in our understanding of the impact of maternal antibody on qualitative or functional infant humoral immunity. Pre-existing antibodies have been shown to induce higher affinity humoral responses, possibly explained by competitive binding in the germinal center (GC) and/or a boost in uptake and antigen presentation, mediated by immune complexes in a Fc glycosylation-dependent manner (Zhang et al, 2013;Lofano et al, 2018;Garg et al, 2019;Langel et al, 2020). Most recently, a randomized control trial in Thailand (NCT02408926) studied term infants who were immunized with either acellular (aP)-or whole cell (wP) pertussis vaccines in infancy; results showed that infants born to women vaccinated in pregnancy had reduced pertussis-specific titres.…”

Section: Once Transferred What Do We Know About the Effect Of Maternmentioning

confidence: 99%

Maternal Immunization: Nature Meets Nurture

Saso

Kampmann

2020

Front. Microbiol.

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Vaccinating women in pregnancy (i.e., maternal immunization) has emerged as a promising tool to tackle infant morbidity and mortality worldwide. This approach nurtures a 'gift of nature,' whereby antibody is transferred from mother to fetus transplacentally during pregnancy, or postnatally in breast milk, thereby providing passive, antigenspecific protection against infections in the first few months of life, a period of increased immune vulnerability for the infant. In this review, we briefly summarize the rationale for maternal immunization programs and the landscape of vaccines currently in use or in the pipeline. We then direct the focus to the underlying biological phenomena, including the main mechanisms by which maternally derived antibody is transferred efficiently to the infant, at the placental interface or in breast milk; important research models and methodological approaches to interrogate these processes, particularly in the context of recent advances in systems vaccinology; the potential biological and clinical impact of high maternal antibody titres on neonatal ontogeny and subsequent infant vaccine responses; and key vaccine-and host-related factors influencing the maternal-infant dyad across different environments. Finally, we outline important gaps in knowledge and suggest future avenues of research on this topic, proposing potential strategies to ensure optimal testing, delivery and implementation of maternal vaccination programs worldwide.

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Preferential Presentation of High-Affinity Immune Complexes in Germinal Centers Can Explain How Passive Immunization Improves the Humoral Response

Cited by 38 publications

References 78 publications

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection

Maternal Immunization: Nature Meets Nurture

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