Biology subjects

Rando, J.

Publications and source records attributed to Rando, J..

6 recordsLinked to original sources

bioRxiv2026

Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

ABSTRACTUnderstanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. ONE SENTENCE SUMMARYBroadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.

immunology↗

bioRxiv2023

Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model

Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/558743v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@17673c8org.highwire.dtl.DTLVardef@1ab61a8org.highwire.dtl.DTLVardef@98781forg.highwire.dtl.DTLVardef@1f63e9b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

A germline-targeting chimpanzee SIV envelope glycoprotein elicits a new class of V2-apex directed cross-neutralizing antibodies

HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germline-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, non-neutralizing antibodies revealed that SCIV-expressed Envs as well as some primary HIV-1 Envs adopted a more open conformation, thereby exposing a conserved V2 epitope that is occluded in closed SIVcpz and HIV-1 Env trimers. These results expand the spectrum of V2-apex targeted antibodies that can contribute to neutralization breadth and identify novel SIV Env platforms for further development as germline-targeting and immunofocusing immunogens. One sentence summaryA cryptic V2 epitope in occluded-open HIV and SIV Env trimers is the target of a new class of V2-directed cross-neutralizing antibodies.

immunology↗

bioRxiv2021

New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention and Cure

Simian-human immunodeficiency virus (SHIV) chimeras contain the HIV-1 envelope (env) gene embedded within an SIVmac proviral backbone. Previously, we showed that substitution of Env residue 375-Ser by bulky aromatic residues enhances Env binding to rhesus CD4 and enables primary or transmitted/founder (T/F) HIV-1 Envs to support efficient SHIV replication in rhesus macaques (RMs). Here, we test this design strategy more broadly by constructing and analyzing SHIVs containing ten strategically selected primary or T/F HIV-1 Envs corresponding to subtypes A, B, C, AE and AG, each with six allelic variants at position 375. All ten SHIVs bearing wildtype Env375 residues replicated efficiently in human CD4+ T cells, but only one of these replicated efficiently in rhesus CD4+ T cells. This was a SHIV whose subtype AE Env naturally contained a bulky aromatic His residue at position 375. Replacement of wildtype Env375 residues by Trp, Tyr, Phe or His in the other nine SHIVs uniformly led to efficient replication in rhesus CD4+ T in vitro and in RMs in vivo. Env375-Trp - the residue found most frequently among SIV strains infecting Old World monkeys - was favored for SHIV replication in RMs, although some SHIVs preferred Env375-Tyr, -His or -Phe. Nine SHIVs containing optimized Env375 alleles were grown large scale in primary activated rhesus CD4+ T cells to serve as challenge stocks in preclinical prevention trials. These virus stocks were genetically homogeneous, native-like in Env antigenicity and tier-2 neutralization sensitivity, transmissible by rectal, vaginal, penile, oral or intravenous inoculation routes, and exhibited acute and early replication kinetics that were indistinguishable from HIV-1 infection in humans. Finally, to expedite future SHIV constructions and eliminate short redundant elements in tat1 and env gp41 that were spontaneously deleted in chronically infected monkeys, we engineered a simplified second-generation SHIV design scheme and validated it in RMs. Overall, our findings demonstrate that SHIVs bearing primary or T/F Envs with bulky aromatic amino acid substitutions at position Env375 consistently replicate in RMs, recapitulating many features of HIV-1 infection in humans. We further show that SHIV challenge stocks grown in primary rhesus CD4+ T cells are efficiently transmitted by mucosal routes common to HIV-1 infection and can be used effectively to test for vaccine efficacy in preclinical monkey trials.

microbiology↗

bioRxiv2020

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

Neutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some cases acquiring substantial breadth. Here we show that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses in rhesus macaques, elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35M. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design. One sentence summaryVirus-antibody coevolution in rhesus macaques recapitulates developmental features of human antibodies.

immunology↗

bioRxiv2019

Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies

In the Western world, 2-5% of pregnant women use selective serotonin reuptake inhibitor (SSRI) antidepressants. There is no consensus on the potential long-term neurodevelopmental outcomes of early SSRI exposure. Our aim was to determine whether there is an overall effect of perinatal SSRI exposure in animals on a spectrum of behavioral domains. After a comprehensive database search in PubMed, PsycINFO, and Web of Science, we included 99 publications. We performed nine meta-analyses and two qualitative syntheses corresponding to different behavioral categories, aggregating data from thousands of animals. We found evidence for reduced activity and exploration behavior (standardized mean difference (SMD) -0.28 [-0.38, -0.18]), more passive stress coping (SMD -0.37 [-0.52, -0.23]), and less efficient sensory processing (SMD -0.37 [-0.69, -0.06]) in SSRI-versus vehicle-exposed animals. No differences were found for anxiety (p=0.06), social behavior, learning and memory, ingestive- and reward behavior, motoric behavior, or reflex and pain sensitivity. Exposure in the period equivalent to the human third trimester was associated with the strongest effects. HighlightsO_LIPerinatal SSRI exposure in rodents alters outcomes in three behavioral domains. C_LIO_LIIt leads to reduced activity, passive stress coping, and weaker sensory processing. C_LIO_LIFemales are understudied but seem to be less vulnerable than males. C_LIO_LIEarly postnatal exposure in rodents leads to the largest effects on behavior. C_LIO_LIThis is equivalent to the third trimester of pregnancy in humans. C_LI

animal behavior and cognition↗