INTRODUCTION

Initiation of ART early after HIV-1 infection results not only in viral suppression but in the preservation of a functional immune system as well. Despite prolonged viral suppression during ART, autologous neutralizing antibody (anAb) responses evolve and mature [1▪]; an indication that both the B and T cell components of the immune system are functional during this period and can mount and sustain an anti-Env response. During subsequent analytic treatment interruption (ATI), anAbs exert pressure to the emerging virus, forcing it to mutate and escape their action. That is, viral variants expressing envelope glycoproteins (Envs) that have accumulated amino acid mutations that minimize the binding of anAbs eventually predominate the viral population during ATI. Re-initiation of ART within weeks, or months in certain cases, of ATI is required to blunt viral replication once again. During ATI not only the virus evolves, but the anAbs evolve as well [1▪]. Nevertheless, broadly neutralizing antibodies (bnAbs) do not develop during the period of ATI. This could be due to a combination of factors, including a) the fact that the short period of ATI is inefficient for the complete maturation of broadly neutralizing antibody responses, which takes many months to years during chronic infection [2–8], b) the rarity of bnAb precursor B cells in humans [9–16], and c) the rarity of viruses expressing Envs with features required to optimally engage germline bnAb precursors [12,17,18]. Env-derived proteins have been designed de novo to optimally engage germline B cell receptor (glBCR) precursors of several known bnAbs [12,19–23]. These novel immunogens, termed ‘germline-targeting’, can efficiently activate naïve B cells that express glBCR bnAb precursors in vivo[24–30]. Combining germline-targeting immunizations during ART with ATI, could be a way to facilitate the maturation of anAb responses towards their broadly neutralizing forms. 

Box 1:

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BROADLY NEUTRALIZING HIV-1 ANTIBODIES DEVELOP DURING HIV-1 INFECTION

An effective HIV-1 vaccine will be one that elicits diverse antiviral immune responses at mucosal sites of HIV-1 entry [31,32]. These responses will include bnAbs of diverse epitope specificities, as escape variants exist for every bnAb specificity. The preventive potential of HIV-1 bnAbs has been demonstrated in passive antibody-administration studies conducted in nonhuman primates prior to SHIV-exposure or in humanized mice actively producing bnAbs prior to HIV-1 exposure [33–35]. Importantly, one HIV-1 bnAb, VRC01, prevented HIV-1 acquisition from sensitive tier 2 viruses in two phase 3 clinical trials (HVTN 703/704) [36]. In addition, initial viral escape from bnAbs is associated with viral fitness costs [37].

Cross-neutralizing HIV-1 antibody activities are detectable in HIV-1 sera and several factors have been associated with their development [5]. Their breadths and potencies vary widely but only a small fraction of chronically infected individuals develop exquisitely potent and broad anti-HIV-1 neutralizing antibodies [2–8]. Generally, bnAb responses become detectable after several years of infection [4]. Over the past decade, numerous new broadly neutralizing monoclonal antibodies (mAbs) have been isolated from HIV-1-infected subjects and were extensively characterized [38–58]. Structural information of such mAbs bound to Env, combined with information of their ontogenies (i.e., their VH/VL derivation) and maturation pathways, vastly improved our understanding of how bnAbs emerge and evolve during HIV-1 infection. This new information led to the development of new hypotheses on how to elicit bnAbs by immunization [31,59–63] and of their potential roles as therapeutic agents [59,64].

THERAPEUTIC USE OF BROADLY NEUTRALIZING mAbs

Although ART suppresses HIV-1 replication and has beneficial effects on morbidity and mortality, it does not lead to viral eradication. Thus, to avoid viral rebound, ART has to be maintained for life which is associated with short- and long-term side effects. bnAb administration has been proposed as an alternative strategy to maintain low viral load for extended periods of time during ATI [64–66]. Indeed, bnAb-administration, concomitant with ATI, can maintain viral loads at very low/undetectable levels for extended periods of time, sometimes months, but eventually viral variants capable of escaping from individual bnAbs emerge [67]. During ART re-initiation, viral loads will again decrease but viral variants that can escape from both anAbs and from bnAbs are now present. Nevertheless, several studies clearly show that bnAb-administration during ATI delays viral rebound, even when the concentrations of bnAbs drop to very low levels. The underlying mechanisms for this interesting observation remain unclear, but CD8+ T cell responses could be involved [68,69]. It is also possible that bnAb-treatment during ATI leads to the development of more effective anti-Env B cell immune responses, as virion-bnAb complexes may be more effectively cross-presented to T cells by antigen-presenting cells [70]. Thus, both the virus and the anti-Env B cells evolve to counter each other during ATI.

IMMUNIZATION DURING ART

The observation that ART initiation during acute or early infection can preserve the functionality of the immune system and limit viral diversification, led to the proposal that vaccination during ART (therapeutic vaccination) may result in the development of antiviral immune responses capable of delaying viral rebound during ATI. Unfortunately, although diverse immunization strategies have been evaluated so far, no real benefit in delaying viral rebound by the vaccine-elicited antiviral responses has been reported [1▪,71,72]. However, these studies either did not include an Env component, or the Env employed was not optimal for the elicitation of bnAbs, so the poor outcome could be due to the lack of generation of bnAbs by these vaccines.

CURRENT EFFORTS TO ELICIT BNABS THROUGH VACCINATION

Three general bnAb-elicitation immunization approaches are being currently pursued in the HIV-1 vaccine field. One approach is the ‘lineage approach’ during which one attempts to reproduce by vaccination the maturation pathway of a specific bnAb clone (‘lineage’) that occurred in an HIV-1-infected individual, by sequentially immunizing healthy individuals with Envs isolated from that infected individual and which are believed to be responsible for that maturation. This is the case for example for bnAbs targeting the apex region of the viral Env [73–75], or those that target the N332 glycan patch of Env [76]. In the lineage approach, the Env immunogens and the order of their administration are believed to be known. Another approach is the ‘germline-targeting approach’ which is based on the observation that not one but a group of glBCRs with similar ontogenies matured in multiple HIV-1+ subjects (infected with different viruses) and produced bnAbs of different amino acid sequences but with similar structural features and identical epitope specificities. This is the case for the anti-CD4-binding site bnAbs belonging to the VRC01-class [50,52]. Here, Envs that activated these glBCRs and the Envs that induced their maturation remain unknown and Env immunogens capable of doing so must be developed de novo[12,19–21] and validated experimentally [24,27,30,77,78]. Therefore, the lineage and germline approaches aim to activate and guide the maturation of specific BCRs that target specific Env epitopes. A third immunization approach can be characterized as ‘agnostic’ as no particular glBCR is targeted, but a specific epitope on Env is targeted [79,80].

ACTIVATING BNAB PRECURSORS THROUGH IMMUNIZATION

Once activated, the glBCR precursors of bnAbs will have to undergo affinity maturation through the accumulation of specific mutations in order to adopt their broadly neutralizing forms [56,74,76,81–84]. This maturation process takes 1–2 years to complete during natural infection during which period virion-associated Envs serve as ‘booster’ immunogens. Virions expressing ‘germline-targeting’ forms of Env initiate this process by activating naïve B cells that express the glBCR precursors of bnAbs. The B cells then enter the germinal center (GC) reaction where their BCRs accumulate mutations (in a mostly random manner). Some of these mutations are conducive to the development of bnAbs, while others are not. It is hypothesized that GC B cells expressing the former BCRs receive secondary stimulatory signals by viral Envs with specific features that allow them to bind these mutated BCRs. This process is repeated until the BCRs have accumulated the entire set of mutations required for their broadly neutralizing forms.

Thus, to elicit bnAbs through immunization, appropriate prime-boost immunizations strategies must be developed (Fig. 1). Here, the first immunogen will activate the glBCR of interest (‘germline-targeting’ immunogen) and heterologous immunogens (‘booster’ immunogens) will be administered, in a specific order, to select and further activate those daughter BCRs that have accumulated mutations conducive with their broadly neutralizing forms [24,25,26,27,29,85–87].

FIGURE 1:

Guided maturation of a bnAb precursor during prime-boost immunizations. To elicit bnAbs through immunization, the first immunogen will activate the glBCR of interest (‘germline-targeting’ immunogen) and heterologous immunogens (‘booster’ immunogens) will be administered, in a specific order, to select and further activate those BCRs that have accumulated appropriate mutations (green).

Env-derived proteins have been designed to optimally activate naïve B cells that express glBCRs of anti-CD4-BS bnAbs [12,19,21], anti-Env apex bnAbs [22,88], or bnAbs that target the N332 neutralization site on Env [23,25]. These germline-targeting Env immunogens activate the targeted B cells in animal models (see above). Importantly, a glVRC01-class germline-targeting immunogen was recently shown to activate germline VRC01-class BCRs in a phase 1 clinical trial [89▪▪].

Although ‘germline-targeting’ immunogens have been designed for a diverse set of bnAbs, the optimal booster immunogens and the order and timing of their administration have not yet been determined. As a result, in only a handful of cases the complete maturation of a bnAb precursor was achieved and this occurred in knock-in mice expressing unphysiologically high frequencies of a single, well defined human glBCR, or after numerous immunizations over a period of ∼2 years [26,86]. In part, this could be due to a less than optimal BCR-activation potential of the booster immunogens used, but other factors are also likely involved.

COMBINING GERMLINE-TARGETING IMMUNIZATIONS WITH ATI

The availability of germline-targeting Env immunogens, gives us the opportunity to evaluate them in combination with ATI. HIV-1-infected subjects on ART would first be immunized with ‘germline-targeting’ Env immunogens and then undergo ATI (Fig. 2). It is expected that during infection, a broad range of nonneutralizing B cell responses would have developed and that viral Env diversity is present. The germline-targeting Env will activate naïve B cells that express the targeted glBCR precursors (Fig. 2a) which will then enter GCs and accumulate somatic mutations. During the subsequent ATI stage (Fig. 2b), emerging viral variants that express Envs with specific features will engage these partially mutated BCRs and provide the necessary booster signals to support and guide their maturation towards their broadly neutralizing forms, similar to what occurs during natural infection. Because of the transient nature of ATI it is not expected that bnAb responses will have enough time to fully develop, although antibodies with some degree of cross-neutralizing potential may develop. Deep sequencing of BCRs from activated Env + B cells, during immunization and during ATI, will confirm the expansion and maturation of glBCR bnAb precursors. Similarly, emerging cross-neutralizing serum antibody activities, and their epitopes, could be detected with the use of specific viruses [90]. Importantly, the parallel sequencing of env from the emerging virus during ATI could lead to the identification of those Envs that guide the maturation of the desired glBCR bnAb precursors. Such Envs could then be employed as booster immunogens in immunization studies of uninfected subjects.

FIGURE 2:

Combining germline-targeting immunization with ATI. (a) B cells expressing BCRs of diverse Env epitope specificities that give rise to nonneutralizing antibodies become activated following HIV-1 infection, but B cells expressing germline BCR precursors of broadly neutralizing antibodies (white B cells) are not activated by the replicating virus, despite the gradual increase in viral Env diversity. (b) Immunization with specifically-designed germline-targeting Env-derived immunogens will lead to the activation of the latter B cells which will enter the germinal center reaction where their B cell receptors will accumulate mutations (Light blue B cells). These B cells will become further activated by specifically viral variants that emerge during ATI and will accumulate additional mutations and become broadly neutralizing (red B cells).

CONCLUSION

The development of ‘germline-targeting’ Env immunogens, the knowledge recently gained on how bnAb responses develop during chronic HIV-1 infection, the information gained on how the anti-HIV-1 immune responses evolve during ART and ATI, along with information on the evolution of HIV-1 Env prior, during and following ATI, and following the administration of broadly neutralizing mAbs, provide us with a unique opportunity to combine germline-targeting Env immunization approaches with viral evolution during ATI. Such studies would inform on whether germline-targeting Env immunogens can activate bnAb precursors in a milieu where preexisting nonbroadly neutralizing antibody responses have been established (i.e., chronic infection + ART); if this activation is as efficient as the one taking place during germline-targeting immunizations of uninfected subjects; whether the antibodies elicited by germline-targeting Env immunogens have any effect on the virus during ATI; whether viral evolution during ATI can further promote the maturation of bnAb precursors towards their neutralizing forms; and, potentially, the identification of natural Envs that can be used as immunogens to promote the maturation of bnAb precursors during immunization of uninfected individuals.

Acknowledgements

I would like to thank Dr Parul Agrawal for any helpful comments and suggestions.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1▪. Esmaeilzadeh E, Etemad B, Lavine CL, et al. Autologous neutralizing antibodies increase with early antiretroviral therapy and shape HIV rebound after treatment interruption. Sci Transl Med 2023; 15:eabq4490. 2. Doria-Rose NA, Klein RM, Daniels MG, et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J Virol 2010; 84:1631–1636. 3. Hraber P, Seaman MS, Bailer RT, et al. Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection. AIDS 2014; 28:163–169. 4. Mikell I, Sather DN, Kalams SA, et al. Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLoS Pathog 2011; 7:e1001251. 5. Sather DN, Armann J, Ching LK, et al. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J Virol 2009; 83:757–769. 6. Stamatatos L, Morris L, Burton DR. Mascola JR: Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nature Medicine 2009; 15:866–870. 7. van Gils MJ, Euler Z, Schweighardt B, et al. Prevalence of cross-reactive HIV-1-neutralizing activity in HIV-1-infected patients with rapid or slow disease progression. AIDS 2009; 23:2405–2414. 8. Simek MD, Rida W, Priddy FH, et al. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J Virol 2009; 83:7337–7348. 9. DeKosky BJ, Lungu OI, Park D, et al. Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires. Proc Natl Acad Sci U S A 2016; 113:E2636–2645. 10. Havenar-Daughton C, Sarkar A, Kulp DW, et al. The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen. Sci Transl Med 2018; 10:eaat0381. 11. He L, Sok D, Azadnia P, et al. Toward a more accurate view of human B-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding. Sci Rep 2014; 4:6778. 12. Jardine J, Julien JP, Menis S, et al. Rational HIV immunogen design to target specific germline B cell receptors. Science 2013; 340:711–716. 13. Lin SG, Ba Z, Du Z, et al. Highly sensitive and unbiased approach for elucidating antibody repertoires. Proc Natl Acad Sci U S A 2016; 113:7846–7851. 14. Yacoob C, Pancera M, Vigdorovich V, et al. Differences in allelic frequency and CDRH3 region limit the engagement of HIV Env Immunogens by putative VRC01 neutralizing antibody precursors. Cell Rep 2016; 17:1560–1570. 15. Huang D, Abbott RK, Havenar-Daughton C, et al. B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models. Proc Natl Acad Sci U S A 2020; 117:22920–22931. 16. Vigdorovich V, Oliver BG, Carbonetti S, et al. Repertoire comparison of the B-cell receptor-encoding loci in humans and rhesus macaques by next-generation sequencing. Clin Transl Immunology 2016; 5:e93. 17. Hoot S, McGuire AT, Cohen KW, et al. Recombinant HIV envelope proteins fail to engage germline versions of anti-CD4bs bNAbs. PLoS Pathog 2013; 9:e1003106. 18. McGuire AT, Glenn JA, Lippy A. Stamatatos L: diverse recombinant HIV-1 Envs fail to activate B cells expressing the germline B cell receptors of the broadly neutralizing anti-HIV-1 antibodies PG9 and 447-52D. J Virol 2014; 88:2645–2657. 19. McGuire AT, Gray MD, Dosenovic P, et al. Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat Commun 2016; 7:10618. 20. McGuire AT, Hoot S, Dreyer AM, et al. Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies. J Exp Med 2013; 210:655–663. 21. Medina-Ramirez M, Garces F, Escolano A, et al. Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. J Exp Med 2017; 214:2573–2590. 22. Andrabi R, Voss JE, Liang CH, et al. Identification of common features in prototype broadly neutralizing antibodies to HIV envelope V2 apex to facilitate vaccine design. Immunity 2015; 43:959–973. 23. Steichen JM, Kulp DW, Tokatlian T, et al. HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. Immunity 2016; 45:483–496. 24. Briney B, Sok D, Jardine JG, et al. Tailored immunogens direct affinity maturation toward HIV neutralizing antibodies. Cell 2016; 166:1459–1470. e1411. 25. Escolano A, Gristick HB, Abernathy ME, et al. Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques. Nature 2019; 570:468–473. 26. Escolano A, Steichen JM, Dosenovic P, et al. Sequential Immunization elicits broadly neutralizing anti-HIV-1 antibodies in Ig knockin mice. Cell 2016; 166:1445–1458. e1412. 27. Parks KR, MacCamy AJ, Trichka J, et al. Overcoming steric restrictions of VRC01 HIV-1 neutralizing antibodies through immunization. Cell Rep 2019; 29:3060–3072. e3067. 28. Saunders KO, Nicely NI, Wiehe K, et al. Vaccine elicitation of high mannose-dependent neutralizing antibodies against the V3-glycan broadly neutralizing epitope in nonhuman primates. Cell Rep 2017; 18:2175–2188. 29. 2022; Knudsen ML, Agrawal P, MacCamy A, et al. Adjuvants influence the maturation of VRC01-like antibodies during immunization. iScience. 25:105473. 30. Dosenovic P, von Boehmer L, Escolano A, et al. Immunization for HIV-1 broadly neutralizing antibodies in human Ig knockin mice. Cell 2015; 161:1505–1515. 31. Burton DR, Ahmed R, Barouch DH, et al. A Blueprint for HIV vaccine discovery. Cell Host Microbe 2012; 12:396–407. 32. Haynes BF, Wiehe K, Borrow P, et al. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies. Nat Rev Immunol 2023; 23:142–158. 33. Balazs AB, Chen J, Hong CM, et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 2012; 481:81–84. 34. Balazs AB, Ouyang Y, Hong CM, et al. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med 2014; 20:296–300. 35. Shingai M, Donau OK, Plishka RJ, et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med 2014; 211:2061–2074. 36. Corey L, Gilbert PB, Juraska M, et al. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N Engl J Med 2021; 384:1003–1014. 37. Lynch RM, Wong P, Tran L, et al. HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies. J Virol 2015; 89:4201–4213. 38. Gorman J, Soto C, Yang MM, et al. Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design. Nat Struct Mol Biol 2016; 23:81–90. 39. McLellan JS, Pancera M, Carrico C, et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 2011; 480:336–343. 40. Gorman J, Chuang GY, Lai YT, et al. Structure of super-potent antibody CAP256-VRC26.25 in complex with HIV-1 envelope reveals a combined mode of trimer-apex recognition. Cell Rep 2020; 31:107488. 41. Pejchal R, Walker LM, Stanfield RL, et al. Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Proc Natl Acad Sci U S A 2010; 107:11483–11488. 42. Julien JP, Lee JH, Cupo A, et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc Natl Acad Sci U S A 2013; 110:4351–4356. 43. Pancera M, Yang Y, Louder MK, et al. N332-Directed broadly neutralizing antibodies use diverse modes of HIV-1 recognition: inferences from heavy-light chain complementation of function. PLoS ONE 2013; 8:e55701. 44. Pejchal R, Doores KJ, Walker LM, et al. A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 2011; 334:1097–1103. 45. Barnes CO, Gristick HB, Freund NT, et al. Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope. Nat Commun 2018; 9:1251. 46. Julien JP, Sok D, Khayat R, et al. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog 2013; 9:e1003342. 47. Mouquet H, Scharf L, Euler Z, et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci U S A 2012; 109:E3268–3277. 48. Barnes CO, Schoofs T, Gnanapragasam PNP, et al. A naturally arising broad and potent CD4-binding site antibody with low somatic mutation. Sci Adv 2022; 8:eab8155. 49. Huang J, Kang BH, Ishida E, Zhou T, et al. Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 2016; 45:1108–1121. 50. Kwong PD, Mascola JR. Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies. Immunity 2012; 37:412–425. 51. Sajadi MM, Dashti A, Rikhtegaran Tehrani Z, et al. Identification of near-pan-neutralizing antibodies against HIV-1 by deconvolution of plasma humoral responses. Cell 2018; 173:1783–1795. e1714. 52. Scheid JF, Mouquet H, Ueberheide B, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 2011; 333:1633–1637. 53. Wu X, Zhou T, Zhu J, et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 2011; 333:1593–1602. 54. Zhou T, Georgiev I, Wu X, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010; 329:811–817. 55. Zhou T, Lynch RM, Chen L, et al. Structural repertoire of HIV-1-neutralizing antibodies targeting the CD4 supersite in 14 donors. Cell 2015; 161:1280–1292. 56. Zhou T, Zhu J, Wu X, et al. Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies. Immunity 2013; 39:245–258. 57. Gristick HB, von Boehmer L, West AP, et al. Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat Struct Mol Biol 2016; 23:906–915. 58. van Schooten J, Farokhi E, Schorcht A, et al. Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein. Nat Commun 2022; 13:4515. 59. Burton DR, Hangartner L. Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu Rev Immunol 2016; 34:635–659. 60. Dimitrov DS. Therapeutic antibodies, vaccines and antibodyomes. MAbs 2010; 2:347–356. 61. Mascola JR, Haynes BF. HIV-1 neutralizing antibodies: understanding nature's pathways. Immunol Rev 2013; 254:225–244. 62. Mascola JR, Montefiori DC. The role of antibodies in HIV vaccines. Annu Rev Immunol 2010; 28:413–444. 63. Stamatatos L, Pancera M, McGuire AT. Germline-targeting immunogens. Immunol Rev 2017; 275:203–216. 64. West AP Jr, Scharf L, Scheid JF, et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 2014; 156:633–648. 65. Caskey M. Broadly neutralizing antibodies for the treatment and prevention of HIV infection. Curr Opin HIV AIDS 2020; 15:49–55. 66. Mavigner M, Chahroudi A. Broadly neutralizing antibodies: ‘the next thing’ to treat children with HIV? Sci Transl Med 2023; 15:eadi0293. 67. Caskey M, Klein F, Lorenzi JC, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 2015; 522:487–491. 68. Nishimura Y, Donau OK, Dias J, et al. Immunotherapy during the acute SHIV infection of macaques confers long-term suppression of viremia. J Exp Med 2021; 218:e20201214. 69. Nishimura Y, Gautam R, Chun TW, et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 2017; 543:559–563. 70. Schoofs T, Klein F, Braunschweig M, et al. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 2016; 352:997–1001. 71. Levy Y, Lacabaratz C, Lhomme E, et al. A randomized placebo-controlled efficacy study of a prime boost therapeutic vaccination strategy in HIV-1-infected individuals: VRI02 ANRS 149 light phase II trial. J Virol 2021; 95:e02165-20. 72. Bailon L, Llano A, Cedeno S, et al. Safety, immunogenicity and effect on viral rebound of HTI vaccines in early treated HIV-1 infection: a randomized, placebo-controlled phase 1 trial. Nat Med 2022; 28:2611–2621. 73. Bhiman JN, Anthony C, Doria-Rose NA, et al. Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies. Nat Med 2015; 21:1332–1336. 74. Doria-Rose NA, Schramm CA, Gorman J, et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 2014; 509:55–62. 75. Rantalainen K, Berndsen ZT, Murrell S, et al. Co-evolution of HIV envelope and apex-targeting neutralizing antibody lineage provides benchmarks for vaccine design. Cell Rep 2018; 23:3249–3261. 76. Bonsignori M, Kreider EF, Fera D, et al. Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. Sci Transl Med 2017; 9:eaai7514. 77. Lin YR, Parks KR, Weidle C, et al. HIV-1 VRC01 germline-targeting immunogens select distinct epitope-specific B Cell receptors. Immunity 2020; 53:840–851. e846. 78. Jardine JG, Ota T, Sok D, et al. HIV-1 VACCINES. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 2015; 349:156–161. 79. Kong R, Xu K, Zhou T, et al. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. Science 2016; 352:828–833. 80. Sastry M, Changela A, Gorman J, et al. Diverse murine vaccinations reveal distinct antibody classes to target fusion peptide and variation in peptide length to improve HIV neutralization. J Virol 2023; 97:e0160422. 81. Klein F, Diskin R, Scheid JF, et al. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 2013; 153:126–138. 82. Umotoy J, Bagaya BS, Joyce C, et al. Rapid and focused maturation of a VRC01-class HIV broadly neutralizing antibody lineage involves both binding and accommodation of the N276-glycan. Immunity 2019; 51:141–154. e146. 83. Wu X, Zhang Z, Schramm CA, et al. Maturation and diversity of the VRC01-antibody lineage over 15 years of chronic HIV-1 infection. Cell 2015; 161:470–485. 84. Moore PL, Gray ES, Wibmer CK, et al. Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nat Med 2012; 18:1688–1692. 85. Caniels TG, Medina-Ramirez M, Zhang J, et al. Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions. Cell Rep Med 2023; 4:101003. 86. Chen X, Zhou T, Schmidt SD, et al. Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth. Immunity 2021; 54:324–339. e328. 87. Tian M, Cheng C, Chen X, et al. Induction of HIV neutralizing antibody lineages in mice with diverse precursor repertoires. Cell 2016; 166:1471–1484. e1418. 88. Voss JE, Andrabi R, McCoy LE, et al. Elicitation of neutralizing antibodies targeting the V2 apex of the HIV envelope trimer in a wild-type animal model. Cell Rep 2018; 22:1103. 89▪▪. Leggat DJ, Cohen KW, Willis JR, et al. Vaccination induces HIV broadly neutralizing antibody precursors in humans. Science 2022; 378:eadd6502. 90. LaBranche CC, McGuire AT, Gray MD, et al. HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. PLoS Pathog 2018; 14:e1007431.