Engineering strategies of Anti-HIV antibody therapeutics in clinical development

Pihlstrom, Nicole; Bournazos, Stylianos

doi:10.1097/coh.0000000000000796

Cited by 2 publications

References 83 publications

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Anticipating HIV viral escape – resistance to active and passive immunization

Williamson,

Lynch,

Moore

2023

Current Opinion in HIV and AIDS

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Purpose Active and passive immunization strategies are challenged by the extraordinary diversity of HIV, and the need for high titers of neutralizing antibodies to confer protective immunity. This review summarises recent studies and the barrier that these interventions will need to overcome to prevent viral resistance. Recent findings Studies from the antibody mediated prevention trial identified a measure of protective titers, finding that higher titers than anticipated will be needed to prevent infection. This benchmark has advanced our ability to predict combinations of broadly neutralizing antibodies (bNAbs) that will provide optimal coverage. To limit escape, these combinations should ensure that the majority of viruses are bound by a minimum of two antibodies. The characterization of currently circulating viruses has revealed increased resistance to some bNAbs over time, highlighting the need for continued surveillance, especially in under-studied populations and subtypes. Active vaccination will face similar challenges in combating diversity, although despite successes in germline targeting, this approach is not yet able to elicit bNAbs. Summary Cumulatively these studies highlight the need to target multiple antibody epitopes for maximum coverage, but also to restrict escape pathways. Successful immunization strategies should anticipate viral escape and devise strategies to counteract this.

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Anticipating HIV viral escape – resistance to active and passive immunization

Williamson,

Lynch,

Moore

2023

Current Opinion in HIV and AIDS

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Assessing bnAb potency in the context of HIV-1 Envelope conformational plasticity

Foulkes,

Friedrich,

Ivan

et al. 2024

Preprint

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The ability of broadly neutralizing antibodies (bnAbs) to interact with the closed, pre-fusion HIV-1 envelope (Env) trimer distinguishes them from weakly neutralizing antibodies (weak-nAbs) that depend on trimer opening to bind. Comparative analysis of neutralization data from the CATNAP database revealed a nuanced relationship between bnAb activity and Env conformational plasticity, with substantial epitope-specific variation of bnAb potency ranging from increased to decreased activity against open, neutralization-sensitive Env. To systematically investigate the impact of Env conformational dynamics on bnAb potency we screened 126 JR-CSF point mutants for generalized neutralization sensitivity to weak-nAbs and plasma from people with chronic HIV-1 infection. 23 mutations at highly conserved sites resulted in neutralization phenotype with high Tier 1 sensitivity, which was associated with de-stabilization of the closed, prefusion conformation. Including 19 of these mutants into a Sensitivity Env mutant panel (SENSE-19), we classified bnAbs according to potency variations in response to trimer opening. To verify that these sensitivity patterns are independent of the in vitro assay system, replication-competent SENSE-19 mutant viruses were tested on primary CD4 T cells. While loss of potency on SENSE-19 was registered for bnAbs recognizing quaternary epitopes on pre-triggered Env, structural destabilization benefitted MPER bnAbs and other inhibitors known to have post-CD4 attachment neutralization activity. Importantly, for certain bnAbs targeting CD4bs, V3-glycan and interface epitopes, particularly low potency variation was noted, suggesting that Env conformational tolerance can be achieved but is not the rule. In summary, SENSE-19 screens revealed distinct Env flexibility tolerance levels between bnAb types that provide mechanistic insights in their function and broaden current neutralization breadth assessments.

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Engineering strategies of Anti-HIV antibody therapeutics in clinical development

Cited by 2 publications

References 83 publications

Anticipating HIV viral escape – resistance to active and passive immunization

Anticipating HIV viral escape – resistance to active and passive immunization

Assessing bnAb potency in the context of HIV-1 Envelope conformational plasticity

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