A minority of HIV-1-infected individuals develop broadly cross-neutralizing (BCN) antibodies, and several of the most potent target glycan-dependent epitopes on the envelope (Env) glycoprotein — the high-mannose patch centered on the N332 glycan at the V3 base and the V2 apex centered on the N160 glycan. Moore et al. (Nature Medicine, 2012) showed in the CAPRISA cohorts that these epitopes can be created during infection: the N332 glycan was absent from the transmitted viruses of two subjects, appeared within months under pressure from strain-specific antibodies, and only then became the target of BCN responses; the N160 glycan followed a similar within-host pattern. The unresolved question is why escape-driven glycan rearrangement elicits BCN lineages in some individuals but not others, whether the glycan state of the transmitted/founder virus predicts eventual neutralization breadth, and how this knowledge should shape glycan-epitope immunogens and antibody combinations covering glycan-diverse transmitted viruses. Cohort-level correlates and single-donor mechanisms have been reported, but the evidence on whether transmission-time glycan state predicts breadth conflicts; the problem remains open.

Background

HIV-1 entry is mediated by the envelope glycoprotein (Env), a trimer of gp120/gp41 heterodimers. Because antibodies bind Env to block infection, the virus cloaks its exposed protein surfaces with a dense shield of host-derived N-linked glycans (sugars covalently attached at asparagine residues within N-X-S/T sequence motifs, where X is any amino acid). A small fraction of infected people eventually develop broadly cross-neutralizing (BCN) antibodies (often called bNAbs in the literature) that overcome this shield and neutralize many unrelated HIV-1 strains ('neutralization breadth'); such antibodies are a central goal of HIV vaccine and passive-immunization research, but vaccination has never reliably elicited them. Two dominant glycan-dependent BCN epitopes are: the high-mannose patch (a cluster of oligomannose-type glycans) or 'V3-glycan supersite' at the base of the third variable loop (V3), centered on the glycan at Env position 332 (numbering referenced to HXB2, a standard laboratory strain used as the alignment reference for residue positions) and recognized by monoclonal antibodies such as PGT128; and the V2 apex at the top of the Env trimer, formed by glycans at positions 156 and 160 together with surrounding protein, recognized by PG9, PGT145 and the CAP256-VRC26 lineage. The virus establishing a new infection is called the transmitted/founder (T/F) virus; early strain-specific antibody responses drive escape mutations in Env, including additions, deletions and shifts of glycans. HIV-1 is classified into subtypes; subtype C dominates the southern-African epidemic. Moore et al. (2012) studied the CAPRISA (Centre for the AIDS Programme of Research in South Africa) acute-infection cohorts of subtype C-infected women and found that in two individuals whose BCN antibodies depended on the N332 glycan, that glycan was absent from the acute virus and appeared within about six months through escape from earlier strain-specific antibodies (a glycan shift from position 334 to 332); the acute viruses were resistant to PGT128, the escaped variants sensitive. Population sequence analysis showed the 332 glycan is significantly under-represented in transmitted compared to chronic subtype C viruses. For two subjects with N160-dependent (V2 apex) BCN responses, the 160 glycan was likewise absent at transmission and later appeared, but the 160 glycan is so conserved that population-level selection on it could not be demonstrated. Crucially, the same paper emphasized that absence of these glycans at transmission is neither required for developing breadth nor sufficient: some individuals develop Asn332-dependent BCN antibodies when the glycan is present at transmission, and some whose viruses evolve the glycan never mount BCN responses. This leaves a bundle of linked open questions — the causal determinants, the predictive value of transmission-time glycan state, the population dynamics of the N160 glycan, and the translational design of immunogens and antibody cocktails — that later work has advanced but not settled.

Problem Statement

The problem, as posed by Moore et al. (2012) and left unresolved by the subsequent literature, is to obtain a causal and predictive account of broadly cross-neutralizing (BCN) antibody elicitation through immune-escape-driven remodeling of the HIV-1 envelope glycan shield, sufficient to guide glycan-epitope-based vaccination and passive immunization (the direct administration of ready-made antibodies). Concretely, an answer must determine: (1) which host and viral factors decide whether immune-escape-driven glycan rearrangement at the glycan-dependent epitopes — the N332-centered V3-glycan supersite and the N160-centered V2 apex — results in the elicitation of BCN antibody lineages in an infected individual, given that neither the presence nor the absence of these glycans on the transmitted/founder virus is either required or sufficient for breadth; (2) whether the glycan state of the transmitted/founder virus (presence or absence of specific glycans such as N332, and the overall completeness of the glycan shield) predicts eventual neutralization breadth across individuals and viral subtypes, resolving the current conflict between cohort studies; (3) what fraction of V2-apex BCN donors show the escape-driven appearance of the highly conserved N160 glycan, and whether viral population data show selection on that N160 glycan — that is, whether its escape-driven appearance is a population-level phenomenon and not confined to individual hosts; and (4) on the basis of (1)–(3), how glycan-epitope-focused immunogens or combinations of antibodies can be designed to provide protective coverage against the diversity of transmitted viruses, particularly subtype C viruses that frequently lack the N332 glycan and resist Asn332-dependent monoclonal antibodies. These four components form one scientific objective, and a complete answer is one that supplies all four: a causal account naming the factors that distinguish individuals who elicit glycan-dependent BCN lineages from those who do not, a stated resolution of the conflict between the cohort studies on whether transmitted/founder glycan state predicts neutralization breadth, a reported frequency of escape-driven N160 appearance among V2-apex BCN donors together with a determination of whether that appearance is under population-level selection, and at least one design rule for glycan-epitope immunogens or antibody combinations that follows from (1)–(3); each component supplies a constraint the others need, and none is separately sufficient.

References

  1. Moore PL, Gray ES, Wibmer CK, Bhiman JN, Nonyane M, Sheward DJ, Hermanus T, Bajimaya S, Tumba NL, Abrahams MR, Lambson BE, Ranchobe N, Ping L, Ngandu N, Abdool Karim Q, Abdool Karim SS, Swanstrom RI, Seaman MS, Williamson C, Morris L (2012). Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape. Nature Medicine 18:1688–1692. doi:10.1038/nm.2985. https://doi.org/10.1038/nm.2985
  2. Wibmer CK, Bhiman JN, Gray ES, Tumba N, Abdool Karim SS, Williamson C, Morris L, Moore PL (2013). Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes. PLoS Pathogens 9:e1003738. doi:10.1371/journal.ppat.1003738. https://doi.org/10.1371/journal.ppat.1003738
  3. van den Kerkhof TL, Feenstra KA, Euler Z, van Gils MJ, Rijsdijk LW, Boeser-Nunnink BD, Heringa J, Schuitemaker H, Sanders RW (2013). HIV-1 envelope glycoprotein signatures that correlate with the development of cross-reactive neutralizing activity. Retrovirology 10:102. doi:10.1186/1742-4690-10-102. https://doi.org/10.1186/1742-4690-10-102
  4. Bhiman JN, Anthony C, Doria-Rose NA, Karimanzira O, Schramm CA, Khoza T, Kitchin D, Botha G, Gorman J, Garrett NJ, Abdool Karim SS, Shapiro L, Williamson C, Kwong PD, Mascola JR, Morris L, Moore PL (2015). Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies. Nature Medicine 21:1332–1336. doi:10.1038/nm.3963. https://doi.org/10.1038/nm.3963
  5. Rusert P, Kouyos RD, Kadelka C, Ebner H, Schanz M, Huber M, Braun DL, Hozé N, Scherrer A, Magnus C, Weber J, Uhr T, Cippa V, Thorball CW, Kuster H, Cavassini M, Bernasconi E, Hoffmann M, Calmy A, Battegay M, Rauch A, Yerly S, Aubert V, Klimkait T, Böni J, Fellay J, Regoes RR, Günthard HF, Trkola A, Swiss HIV Cohort Study, Bucher HC, Ciuffi A, Dollenmaier G, Egger M, Elzi L, Fehr J, Furrer H, Fux CA, Haerry D, Hasse B, Hirsch HH, Hösli I, Kahlert C, Kaiser L, Keiser O, Kovari H, Ledergerber B, Martinetti G, Martinez de Tejada B, Marzolini C, Metzner KJ, Müller N, Nicca D, Pantaleo G, Paioni P, Rudin C, Schmid P, Speck R, Stöckle M, Tarr P, Vernazza P, Wandeler G, Weber R (2016). Determinants of HIV-1 broadly neutralizing antibody induction. Nature Medicine 22:1260–1267. doi:10.1038/nm.4187. https://doi.org/10.1038/nm.4187
  6. Rademeyer C, Korber B, Seaman MS, Giorgi EE, Thebus R, Robles A, Sheward DJ, Wagh K, Garrity J, Carey BR, Gao H, Greene KM, Tang H, Bandawe GP, Marais JC, Diphoko TE, Hraber P, Tumba N, Moore PL, Gray GE, Kublin J, McElrath MJ, Vermeulen M, Middelkoop K, Bekker LG, Hoelscher M, Maboko L, Makhema J, Robb ML, Abdool Karim S, Abdool Karim Q, Kim JH, Hahn BH, Gao F, Swanstrom R, Morris L, Montefiori DC, Williamson C (2016). Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition: implications for active and passive immunization. PLoS Pathogens 12:e1005742. doi:10.1371/journal.ppat.1005742. https://doi.org/10.1371/journal.ppat.1005742
  7. Andrabi R, Su CY, Liang CH, Shivatare SS, Briney B, Voss JE, Nawazi SK, Wu CY, Wong CH, Burton DR (2017). Glycans function as anchors for antibodies and help drive HIV broadly neutralizing antibody development. Immunity 47:524–537. doi:10.1016/j.immuni.2017.08.006. https://doi.org/10.1016/j.immuni.2017.08.006
  8. Wagh K, Kreider EF, Li Y, Barbian HJ, Learn GH, Giorgi E, Hraber PT, Decker TG, Smith AG, Gondim MV, Gillis L, Wandzilak J, Chuang GY, Rawi R, Cai F, Pellegrino P, Williams I, Overbaugh J, Gao F, Kwong PD, Haynes BF, Shaw GM, Borrow P, Seaman MS, Hahn BH, Korber B (2018). Completeness of HIV-1 Envelope glycan shield at transmission determines neutralization breadth. Cell Reports 25:893–908.e7. doi:10.1016/j.celrep.2018.09.087. https://doi.org/10.1016/j.celrep.2018.09.087
  9. Mabvakure BM, Scheepers C, Garrett N, Abdool Karim S, Williamson C, Morris L, Moore PL (2019). Positive selection at key residues in the HIV envelope distinguishes broad and strain-specific plasma neutralizing antibodies. Journal of Virology 93:e01685-18. doi:10.1128/JVI.01685-18. https://doi.org/10.1128/JVI.01685-18
  10. Li Y, Bai H, Sanders-Buell E, Dussupt V, Townsley S, Donofrio G, Bose M, O'Sullivan AM, Kibuuka H, Maganga L, Nitayaphan S, Kosgei J, Pitisuttithum P, Rerks-Ngarm S, Eller LA, Michael NL, Robb ML, Ake J, Vasan S, Tovanabutra S, Krebs SJ, Rolland M (2021). Limited evidence for a relationship between HIV-1 glycan shield features in early infection and the development of neutralization breadth. Journal of Virology 95:e00797-21. doi:10.1128/JVI.00797-21. https://doi.org/10.1128/JVI.00797-21
  11. Lewitus E, Townsley SM, Li Y, Donofrio GC, Dearlove BL, Bai H, Sanders-Buell E, O'Sullivan AM, Bose M, Kibuuka H, Maganga L, Nitayaphan S, Sawe FK, Eller LA, Michael NL, Polonis VR, Ake J, Vasan S, Robb ML, Tovanabutra S, Krebs SJ, Rolland M (2022). HIV-1 infections with multiple founders associate with the development of neutralization breadth. PLoS Pathogens 18:e1010369. doi:10.1371/journal.ppat.1010369. https://doi.org/10.1371/journal.ppat.1010369
  12. Corey L, Gilbert PB, Juraska M, Montefiori DC, Morris L, Karuna ST, Edupuganti S, Mgodi NM, deCamp AC, Rudnicki E, Huang Y, Gonzales P, Cabello R, Orrell C, Lama JR, Laher F, Lazarus EM, Sanchez J, Frank I, Hinojosa J, Sobieszczyk ME, Marshall KE, Mukwekwerere PG, Makhema J, Baden LR, Mullins JI, Williamson C, Hural J, McElrath MJ, Bentley C, Takuva S, Gomez Lorenzo MM, Burns DN, Espy N, Randhawa AK, Kochar N, Piwowar-Manning E, Donnell DJ, Sista N, Andrew P, Kublin JG, Gray G, Ledgerwood JE, Mascola JR, Cohen MS (2021). Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. New England Journal of Medicine 384:1003–1014. doi:10.1056/NEJMoa2031738. https://doi.org/10.1056/NEJMoa2031738
  13. Schommers P, Kim DS, Schlotz M, Kreer C, Eggeling R, Hake A, Stecher M, Park J, Radford CE, Dingens AS, Ercanoglu MS, Gruell H, Odidika S, Dahlhaus M, Gieselmann L, Ahmadov E, Lawong RY, Heger E, Knops E, Wyen C, Kümmerle T, Römer K, Scholten S, Wolf T, Stephan C, Suárez I, Raju N, Adhikari A, Esser S, Streeck H, Duerr R, Nanfack AJ, Zolla-Pazner S, Geldmacher C, Geisenberger O, Kroidl A, William W, Maganga L, Ntinginya NE, Georgiev IS, Vehreschild JJ, Hoelscher M, Fätkenheuer G, Lavinder JJ, Bloom JD, Seaman MS, Lehmann C, Pfeifer N, Georgiou G, Klein F (2023). Dynamics and durability of HIV-1 neutralization are determined by viral replication. Nature Medicine 29:2763–2774. doi:10.1038/s41591-023-02582-3. https://doi.org/10.1038/s41591-023-02582-3
  14. Mahomed S, Garrett N, Capparelli EV, Osman F, Mkhize N, Harkoo I, Gengiah TN, Mansoor LE, Baxter C, Archary D, Yende-Zuma N, Samsunder N, Carlton K, Narpala S, McDermott AB, Doria-Rose NA, Moore PL, Morris L, Abdool Karim Q, Mascola JR, Abdool Karim SS (2023). Safety and pharmacokinetics of escalating doses of neutralising monoclonal antibody CAP256V2LS administered with and without VRC07-523LS in HIV-negative women in South Africa (CAPRISA 012B): a phase 1, dose-escalation, randomised controlled trial. The Lancet HIV 10:e230–e243. doi:10.1016/S2352-3018(23)00003-6. https://doi.org/10.1016/S2352-3018(23)00003-6
  15. Habib R, Roark RS, Li H, Connell AJ, Hogarty MP, Wagh K, Wang S, Marchitto L, Skelly AN, Carey JW, Sowers KJ, Ayyanathan K, Plante SJ, Bibollet-Ruche F, Park Y, Agostino CJ, Singh A, Martella CL, Lewis E, Rando JM, Chohan N, Lora J, Ding W, Campion MS, Zhao C, Liu W, Li Y, Li X, Liang B, Chowdhury RR, Amereh K, Van Itallie E, Sheng Z, Ghosh AR, Bar KJ, Williams WB, Wiehe K, Saunders KO, Edwards RJ, Cain DW, Lewis M, Batista FD, Burton DR, Andrabi R, Kulp DW, Haynes BF, Korber B, Shapiro L, Kwong PD, Hahn BH, Shaw GM (2025). Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development. bioRxiv 2025.05.03.652068 (preprint). doi:10.1101/2025.05.03.652068. https://doi.org/10.1101/2025.05.03.652068
  16. Relano-Rodriguez I, Du J, Lin ZJ, Kerwin M, Tarquis-Medina M, Urbano E, Cui J, Watkins M, Lavine CL, Zhao P, Habib R, Agostino C, Ghosh S, Park J, Boroughs C, Walsh AA, Melo MB, Shukla N, Shaw GM, Hahn BH, Irvine DJ, Wells L, Weiner DB, Seaman MS, Kulp DW, Veazey RS, Pallesen J, Escolano A (2026). Rapid elicitation of neutralizing Asn332-glycan-independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates. Nature Immunology 27:586–599. doi:10.1038/s41590-025-02408-z. https://doi.org/10.1038/s41590-025-02408-z