Mouse models with human antibody repertoires for inducing multiple lineages of HIV-1 broadly neutralizing antibodies
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eLife Assessment
This important study advances the HIV-1 vaccine development field by establishing six humanized immunoglobulin knock-in mouse models to facilitate the design and evaluation of HIV-1 vaccines. The evidence supporting the claims is compelling, with robust genetic engineering and rigorous baseline sequencing data, while additional assessment of BCR pairing, expression, and repertoire diversity would round out the characterization of these models. These mice offer the field a rich resource to evaluate vaccine candidates that induce broadly neutralizing antibodies against major epitopes of the HIV-1 envelope protein.
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Abstract
The complementarity determining region (CDR) 1, 2 and 3 of antibodies are the principal antigen contact sites. The heavy chain CDR3 (CDR H3) is highly variable, because it includes random nucleotide additions by the terminal deoxynucleotidyl transferase (TdT). Some broadly neutralizing antibodies (bnAbs) against the human immunodeficiency virus-1 (HIV-1) rely heavily on CDR H3 to recognize conserved epitopes on HIV-1 Envelope (Env) protein. Elicitation of comparable bnAbs is a prime goal of HIV-1 vaccine development, but the shortage of precursor antibodies with suitable CDR H3s in human repertoire is a major challenge for immunogen design. To aid this effort, we generated six mouse models for inducing bnAbs against major HIV-1 Env epitopes. In each mouse model, the immunoglobulin heavy and light chain loci were engineered to predominantly rearrange the germline V, D and J segments of a bnAb lineage. Owing to CDR3 diversity, only a small subset of the V(D)J recombination products may encode variable regions that can engage bnAb epitopes with sufficient affinity to initiate immune response. Therefore, these mouse models can be used to test and optimize immunization strategies to induce bnAbs from rare and diverse precursors in complex antibody repertoires.
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eLife Assessment
This important study advances the HIV-1 vaccine development field by establishing six humanized immunoglobulin knock-in mouse models to facilitate the design and evaluation of HIV-1 vaccines. The evidence supporting the claims is compelling, with robust genetic engineering and rigorous baseline sequencing data, while additional assessment of BCR pairing, expression, and repertoire diversity would round out the characterization of these models. These mice offer the field a rich resource to evaluate vaccine candidates that induce broadly neutralizing antibodies against major epitopes of the HIV-1 envelope protein.
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Reviewer #1 (Public review):
Summary
In "Mouse models with human antibody repertoires for inducing multiple lineages of HIV-1 broadly neutralizing antibodies", Tian et al. report the production of 6 humanized mouse models to support HIV-1 vaccine design studies aiming to induce different classes of broadly neutralizing antibodies.
These mice were designed to express immunoglobulin genes of human bNAbs targeting four different conserved epitopes of the HIV-1 Envelope while allowing the development of CDRH3 and CDRL3 diversity during gene rearrangements.
Strengths:
(1) The manuscript is clearly written, and findings are clearly presented with self-explanatory figures. The Introduction and Discussion sections provide very valuable context to understand the relevance of these mouse models and are accessible to a general reader. It is …
Reviewer #1 (Public review):
Summary
In "Mouse models with human antibody repertoires for inducing multiple lineages of HIV-1 broadly neutralizing antibodies", Tian et al. report the production of 6 humanized mouse models to support HIV-1 vaccine design studies aiming to induce different classes of broadly neutralizing antibodies.
These mice were designed to express immunoglobulin genes of human bNAbs targeting four different conserved epitopes of the HIV-1 Envelope while allowing the development of CDRH3 and CDRL3 diversity during gene rearrangements.
Strengths:
(1) The manuscript is clearly written, and findings are clearly presented with self-explanatory figures. The Introduction and Discussion sections provide very valuable context to understand the relevance of these mouse models and are accessible to a general reader. It is appreciated that the data are presented with transparency, highlighting both strengths and weaknesses of the mouse models.
(2) The characterization of the mouse models is overall thorough and rigorous. Immunization data to confirm functionality are not presented; however, it is understandable that this information will be presented in the context of subsequent studies. The authors indicate that these mice have been distributed to different teams.
(3) These mice will be very valuable tools for the HIV-1 vaccine community to evaluate vaccine candidates in a "closer-to-human" setting that allows a certain level of polyclonality while using human immunoglobulin genes.
Weaknesses:
(1) The authors investigate the use of the knocked-in human immunoglobulin genes in heavy chains and light chains and provide the frequency of productive rearrangements using these genes. However, there is no information about the frequency of the right heavy-light chain pairs. This information would be important to calculate the real frequencies of potential bNAb precursors in these mouse models.
(2) The authors use HTGTS-rep-seq to investigate immunoglobulin gene rearrangements at the genomic DNA level. This method is very useful for analyzing gene recombination because it provides information about both productive and non-productive rearrangements. However, this method does not provide information about BCR expression, and it is not optimal for investigating repertoire composition. BCR expression would provide a more rigorous characterization of the mice and confirm functionality.
(3) The goal of this study was to produce models that could provide a diverse bNAb-like repertoire. Specific quantification of the diversity of the repertoire is not provided. The study does not provide information about the sequences that do not use the intended genes.
Overall, the availability of these humanized mouse models will be very valuable for the HIV-1 vaccine community and will provide valuable pre-clinical models to advance the design and testing of vaccine candidates.
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Reviewer #2 (Public review):
Tian & colleagues generate and characterize six novel humanized mouse models engineered to express precursor human antibody repertoires for inducing multiple lineages of broadly neutralizing antibodies (bnAbs) against HIV-1. Building on prior "VRC01-class" proof-of-concept work, this manuscript advances the field by demonstrating the value and suitability of these sophisticated models for testing the ability of vaccine candidates to induce bnAbs. By utilizing flow cytometry and HGTS sequencing techniques, the authors demonstrate that the targeted bnAb minigenes successfully undergo physiological V(D)J recombination and junctional diversification. Despite phenotypic heterogeneity in B-cell development, they show that these models reproducibly produce diverse repertoires enriched for functional humanized …
Reviewer #2 (Public review):
Tian & colleagues generate and characterize six novel humanized mouse models engineered to express precursor human antibody repertoires for inducing multiple lineages of broadly neutralizing antibodies (bnAbs) against HIV-1. Building on prior "VRC01-class" proof-of-concept work, this manuscript advances the field by demonstrating the value and suitability of these sophisticated models for testing the ability of vaccine candidates to induce bnAbs. By utilizing flow cytometry and HGTS sequencing techniques, the authors demonstrate that the targeted bnAb minigenes successfully undergo physiological V(D)J recombination and junctional diversification. Despite phenotypic heterogeneity in B-cell development, they show that these models reproducibly produce diverse repertoires enriched for functional humanized B-cell receptors expressing knock-in-derived bnAb precursor rearrangements, a subset of which yield the long, correctly charged CDRH3 loops required to target conserved but glycan-shielded bnAb epitopes. This achievement successfully overcomes a major vaccine testing bottleneck by providing a pool of patient-deduced precursor configurations in sufficient amounts to reliably study how subsequent somatic mutation events are induced by candidate vaccine protocols (with the potential exception of the PG9 model). Crucially, the comparative utilization of Kymab data serves as an excellent control to demonstrate the extreme rarity of bnAb rearrangements in fully locus-humanized mice, beautifully illustrating the design limitations of humanized models without adjusting for the much smaller repertoires of mice. Finally, the discussion is nuanced and well-written, including articulating the models' free availability and highlighting why these small-animal systems are complementary-and sometimes essential-in relation to rhesus macaque systems.
The paper's conclusions are robustly data-supported, with the only slight weakness being that the Kymab data were extrapolated rather than derived from actual head-to-head analyses. The comments below predominantly aim to provide further context and clarity-mainly in the abstract, results, and discussion sections-to this already excellent, highly detailed study. Refining the text clarity and phenotypic observations will further polish this impressive manuscript.
(1) Abstract Clarity:
Concluding sentences should incorporate the discussion's explanation: finding natively low-frequency precursors in standard humanized locus mice is statistically prohibitive due to their smaller absolute B-cell compartment. These models bypass this restriction by maximizing relevant segment expression to expand the functional CDR3 search space.(2) Results (Line 183, BG18 expansion):
The intriguing expanded B1 cell population warrants more conservative commentary regarding genuine autoreactivity versus other possibilities, such as hyperactive baseline signaling via autophosphorylation (as shown by Hassan Jumaa for certain HC/LC clonotypes). While beyond this manuscript's scope, these mechanisms are differentiable via calcium flux assays with general anti-BCR signaling reagents.(3) Results (p15/Line 324, PCT64/CH235 Vκ Allelic Architecture):
The text states that lacking a recombination cassette caused hVκ3-20 to account for only a fraction of rearrangements. While Figure 1B's general engineering feature (tandem reverse hJκ-RSS 23 and 12 RSS hJκ) implies human Vκ should predominate everywhere, Figure 1C suggests hVκ3-20's low representation in CH235 and PCT64 models stems from being introduced differently-specifically via pre-rearranged minigenes rather than unaltered RSS orientations in an unrearranged cassette. The authors should clarify this point in the text and/or Figure 1.(4) Results (p14, Clever Engineering of λLC rearranging mice):
Replacing mCκ with hCλ3 is a clever genetic trick and an important proof of concept for stably accommodating a human lambda rearranging light chain cassette within the mouse kappa locus. This excellent methodological highlight deserves prominent recognition as a template for other model developers. I suggest giving this further play in the discussion.(5) Discussion (Model Comparisons & Baseline Resolution):
The authors aptly compare these humanized mice to macaques; in addition to their superior scalability, they point out that macaques don't recapitulate human-specific bnAb-relevant configurations in certain instances (like lacking the VH1-2 minigene for VRC01-class responses, or utilizing germline D segments that favor V2 apex responses, potentially overestimating human responses). To further enhance nuance, referencing other prior review KI model literature on this topic (some published by these authors) would be beneficial. For context, KI-derived adoptive transfer models offer more potential diversity (thus, 'higher bar' off-target response testing) and frequency control but are restricted to short priming studies. Conversely, the rearranging models in this study support full vaccine regimens and generate multiple variant bnAb precursors to compare potential in vivo response plasticity.(6) Discussion (Baseline phenotypes):
One limitation of the cellular flow data, albeit beyond the manuscript's current scope, is that the baseline phenotypes predominantly reflect variations of a fixed pair of V(D)J rearrangements, rather than bona fide patient-derived UCA bnAb precursors with correct charges/lengths. To help resolve pre-antigenic functional signaling boundaries and thus potentially aid immunogen design, the discussion could note how future work could aim to use techniques like single-cell transcriptomics to map expressed selection signatures of bnAb precursor paired V(D)J's to rule out anergy or survival/death gene signatures.(7) Discussion (PG9 Model & HCDR3 Length Constraints):
While the PG9 model's failure to produce bona fide precursors is unsurprising given its long HCDR3, the authors should provide a bit more detail as to whether a subset of PG9 variants with slightly shorter HCDR3s are permissive for bnAb production (analogous to DH511/10E8). Providing the specific HCDR3 sizes generated by this model in relation to recently discovered monkey antibodies-which are shorter/different but function like PG9 bnAbs (e.g., Guenega et al Nature 2026) - would offer excellent context. Such related lineage and/or lineage precursor variants could serve as structural alternatives, and highlighting how these length constraints impact selection provides vital boundary conditions for the immunogen design field when planning germline-targeting regimens. -
Author response:
Reviewer #1 (Public review):
(1) The authors investigate the use of the knocked-in human immunoglobulin genes in heavy chains and light chains and provide the frequency of productive rearrangements using these genes. However, there is no information about the frequency of the right heavy-light chain pairs. This information would be important to calculate the real frequencies of potential bNAb precursors in these mouse models.
We acknowledge that our bulk sequencing-based repertoire analysis does not assess the pairing of immunoglobulin (Ig) heavy and light chains. To add this information, we plan to sort IgM+IgDhi naive B cells from the mouse models and use single-cell RT-PCR to analyze paired heavy and light chains from individual B cells. Since the assay detects Ig transcripts, it will also address comment #2 …
Author response:
Reviewer #1 (Public review):
(1) The authors investigate the use of the knocked-in human immunoglobulin genes in heavy chains and light chains and provide the frequency of productive rearrangements using these genes. However, there is no information about the frequency of the right heavy-light chain pairs. This information would be important to calculate the real frequencies of potential bNAb precursors in these mouse models.
We acknowledge that our bulk sequencing-based repertoire analysis does not assess the pairing of immunoglobulin (Ig) heavy and light chains. To add this information, we plan to sort IgM+IgDhi naive B cells from the mouse models and use single-cell RT-PCR to analyze paired heavy and light chains from individual B cells. Since the assay detects Ig transcripts, it will also address comment #2 about the lack of expression data for the human Ig segments.
The main goal of the single-cell RT-PCR experiment is to verify that the human Ig segments in the mouse models can be expressed as B cell receptors (BCRs) in naive B cells. However, because of its low-throughput nature, the assay is unlikely to be sensitive enough for detecting bnAb precursors. As shown in Figure 5G, the frequencies of bnAb-like CDR H3s for DH270, BG18 and PCT64 are in the range of 10-4. The frequencies of paired bnAb-like heavy and light chains will be even lower. It will be difficult to robustly measure the frequencies of such rare BCRs even with 10x Genomic single-cell sequencing. For reference, 10x Genomic sequencing of B cells from 10E8 KI mice yielded 1026 heavy and light chain pairs (1). The sample size was adequate for analyzing light chains paired with the pre-rearranged 10E8 heavy chain, which is expressed in most B cells. The sequencing depth will be insufficient for detecting rare bnAb precursors in the rearranging mouse models of this study. Deep bulk sequencing data were used to calculate bnAb precursor frequencies in our previous VRC01 mouse models and in humans and nonhuman primates (2-8). It is possible to enrich bnAb precursors for single-cell analysis by sorting epitope-specific B cells (9-11). However, this method requires sorting probes that exhibit high affinity and selectivity for bnAb precursors. We believe immunization of the mouse models will be the most direct and definitive way to detect bnAb precursors and test their functions in these mouse models. As mentioned in the manuscript, we have already provided the mouse models to several investigators for immunization experiments.
(2) The authors use HTGTS-rep-seq to investigate immunoglobulin gene rearrangements at the genomic DNA level. This method is very useful for analyzing gene recombination because it provides information about both productive and non-productive rearrangements. However, this method does not provide information about BCR expression, and it is not optimal for investigating repertoire composition. BCR expression would provide a more rigorous characterization of the mice and confirm functionality.
It is true that HTGTS-rep-seq does not directly show the expression of productive rearrangements. As outlined in our response to comment #1, we plan to perform single-cell RT-PCR to confirm the expression of the integrated human Ig segments in IgM+IgDhi B cells.
We have used HTGTS-rep-seq extensively to analyze V(D)J rearrangements. Overall, the outcomes of the repertoire analysis correlated well with functional assays of BCR expression. For example, we identified VRC01-class heavy and light chains in VRC01 mouse models with HTGTS-rep-seq; correspondingly, immunization of the mouse models elicited VRC01-class antibodies (7, 8, 10). As another example, we used HTGTS-rep-seq to characterize V(D)J rearrangements at different stages of B cell development (12). The ratio of productive/nonproductive V(D)J rearrangements increases as B cells mature. The correlation suggests that the productive rearrangements, as detected by HTGTS-rep-seq, are selected by virtue of their expression as BCRs, which are required for B cell maturation and survival.
(3) The goal of this study was to produce models that could provide a diverse bNAb-like repertoire. Specific quantification of the diversity of the repertoire is not provided. The study does not provide information about the sequences that do not use the intended genes.
In our previous analysis of the VRC01 mouse models, we calculated the proportion of unique CDR3s and CDR3 overlap among different animals and used these parameters to represent repertoire diversity (7, 8). We will perform the same analysis for the six mouse models in this study. The V(D)J rearrangements that do not use the human Ig segments are composed of mouse Ig segments, and we will show repertoire analysis of these rearrangements in the revised manuscript.
Reviewer #2 (Public review):
(1) Abstract Clarity:
Concluding sentences should incorporate the discussion's explanation: finding natively low-frequency precursors in standard humanized locus mice is statistically prohibitive due to their smaller absolute B-cell compartment. These models bypass this restriction by maximizing relevant segment expression to expand the functional CDR3 search space.
We will make the suggested change in Abstract.
(2) Results (Line 183, BG18 expansion):
The intriguing expanded B1 cell population warrants more conservative commentary regarding genuine autoreactivity versus other possibilities, such as hyperactive baseline signaling via autophosphorylation (as shown by Hassan Jumaa for certain HC/LC clonotypes). While beyond this manuscript's scope, these mechanisms are differentiable via calcium flux assays with general anti-BCR signaling reagents.
We are currently examining the cause of B1 cell expansion in the BG18 model. Our preliminary data suggest that some of the B1 cells express autoreactive antibodies, but more work is needed to reach a conclusion. Until then, we are open to alternative possibilities, as suggested.
(3) Results (p15/Line 324, PCT64/CH235 Vκ Allelic Architecture):
The text states that lacking a recombination cassette caused hVκ3-20 to account for only a fraction of rearrangements. While Figure 1B's general engineering feature (tandem reverse hJκ-RSS 23 and 12 RSS hJκ) implies human Vκ should predominate everywhere, Figure 1C suggests hVκ3-20's low representation in CH235 and PCT64 models stems from being introduced differently-specifically via pre-rearranged minigenes rather than unaltered RSS orientations in an unrearranged cassette. The authors should clarify this point in the text and/or Figure 1.
The recombination cassette, as diagrammed in Figure 1B, is not in the CH235 and PCT64 models. Instead, the hVk3-20 allele in these models was derived from one of the previous VRC01 mouse models (7). As described in the Luo et al paper (7), hVk3-20 replaces mouse Vk3-7 in the Igk locus, but all the other mouse Vk segments are intact and functional. In this configuration, hVk3-20 rearranges as one of the Vk segments in Igk allele and accounts for about 10% of total Igk rearrangements. We will clarify this point in the revision.
(4) Results (p14, Clever Engineering of λLC rearranging mice):
Replacing mCκ with hCλ3 is a clever genetic trick and an important proof of concept for stably accommodating a human lambda rearranging light chain cassette within the mouse kappa locus. This excellent methodological highlight deserves prominent recognition as a template for other model developers. I suggest giving this further play in the discussion.
We will highlight this design in the discussion.
(5) Discussion (Model Comparisons & Baseline Resolution):
The authors aptly compare these humanized mice to macaques; in addition to their superior scalability, they point out that macaques don't recapitulate human-specific bnAb-relevant configurations in certain instances (like lacking the VH1-2 minigene for VRC01-class responses, or utilizing germline D segments that favor V2 apex responses, potentially overestimating human responses). To further enhance nuance, referencing other prior review KI model literature on this topic (some published by these authors) would be beneficial. For context, KI-derived adoptive transfer models offer more potential diversity (thus, 'higher bar' off-target response testing) and frequency control but are restricted to short priming studies. Conversely, the rearranging models in this study support full vaccine regimens and generate multiple variant bnAb precursors to compare potential in vivo response plasticity.
As suggested, we will include additional references and comparisons of the Ig humanized mouse models with KI mice. The reviewer raised an important point about off-target responses. Adoptive transfer models have the full mouse antibody repertoire. By comparison, the antibody repertoires of the Ig-humanized mouse models are dominated by a select set of human Ig segments, with minimal contribution from mouse antibodies. From this perspective, the adoptive transfer model provides a more diverse range of potential off-target antibodies. On the other hand, the Ig-humanized mouse models may be superior to wild-type mice in producing antibodies against the immunogenic glycan holes in envelopes (13). Reaching these glycan holes may require sufficient CDR H3 length, and based on CDR H3 length distribution, Ig-humanized mouse models could be more capable of recapitulating this type of off-target response than wild-type mice.
(6) Discussion (Baseline phenotypes):
One limitation of the cellular flow data, albeit beyond the manuscript's current scope, is that the baseline phenotypes predominantly reflect variations of a fixed pair of V(D)J rearrangements, rather than bona fide patient-derived UCA bnAb precursors with correct charges/lengths. To help resolve pre-antigenic functional signaling boundaries and thus potentially aid immunogen design, the discussion could note how future work could aim to use techniques like single-cell transcriptomics to map expressed selection signatures of bnAb precursor paired V(D)J's to rule out anergy or survival/death gene signatures.
The reviewer is correct that the surface phenotypes of rare bnAb precursor B cells, such as low BCR levels on anergic B cells, may not be apparent in the bulk flow cytometric analysis. Single-cell transcription signature analysis would be a high-resolution method to analyze bnAb precursor B cells. The technical challenge is low bnAb precursor frequencies, and enrichment of bnAb precursors by immunogen sorting may be the necessary for their detection. We will discuss this point in the revised manuscript.
(7) Discussion (PG9 Model & HCDR3 Length Constraints):
While the PG9 model's failure to produce bona fide precursors is unsurprising given its long HCDR3, the authors should provide a bit more detail as to whether a subset of PG9 variants with slightly shorter HCDR3s are permissive for bnAb production (analogous to DH511/10E8). Providing the specific HCDR3 sizes generated by this model in relation to recently discovered monkey antibodies-which are shorter/different but function like PG9 bnAbs (e.g., Guenega et al Nature 2026) - would offer excellent context. Such related lineage and/or lineage precursor variants could serve as structural alternatives, and highlighting how these length constraints impact selection provides vital boundary conditions for the immunogen design field when planning germline-targeting regimens.
The suggested recent studies (14-17) showed that V2 apex targeting is achievable with relatively shorter CDR H3s (22-25aa), which are within reach in the PG9 mouse model. However, the rhesus antibodies utilize IGHD3-15 with optimal V2 apex targeting motif. It remains to be determined whether hD3-3-based antibodies with comparable CDR H3 length would function similarly. We will incorporate the new information from rhesus immunization studies into the discussion.
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