HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate
Abstract HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1 infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the pre-hairpin intermediate, is not well understood. Here we show that two inhibitors targeting distinct highly-conserved regions of the pre-hairpin intermediate have strikingly consistent neutralization potencies (within ∼100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 11. Okt. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bell, Benjamin N. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.10.06.511062 |
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| 245 | 1 | 0 | |a HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate |
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| 520 | |a Abstract HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1 infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the pre-hairpin intermediate, is not well understood. Here we show that two inhibitors targeting distinct highly-conserved regions of the pre-hairpin intermediate have strikingly consistent neutralization potencies (within ∼100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation. | ||
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