Biology subjects

York, T.

Publications and source records attributed to York, T..

5 recordsLinked to original sources

bioRxiv2025

VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials

Broadly neutralizing antibodies (bnAbs) show promise in HIV prevention, yet viral escape remains a challenge. In the Antibody Mediated Prevention (AMP) trials, the CD4 binding site (CD4bs) bNAb VRC01 blocked acquisition by VRC01-sensitive strains. However, its influence on viral evolution post-acquisition is not fully understood. Here we analyzed >12,000 HIV env sequences from 47 participants from the AMP trials, identifying VRC01-mediated de novo escape mutations in 8 of 26 VRC01-treated participants but none in 21 placebo participants. These mutations were found at very low frequency (<1%) in global viruses. Escape mutations, primarily located in the Loop-D and {beta}23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs, while more potent CD4bs bnAbs like N6 and 1-18 largely retained their activity. Our findings demonstrate that prophylactic VRC01 can select for viral escape after infection, underscoring the need for next-generation bnAbs with improved breadth and potency to enhance durability and efficacy of antibody-based HIV prevention.

microbiology↗

bioRxiv2025

Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection

Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts (median 4 days) between the last-negative and first-positive RNA tests, we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 38% in these as well as placebo recipients from the AMP trials was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. Viral populations exhibited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.

microbiology↗

bioRxiv2025

Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials

In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-{Delta}pol (2.5 kb) and 53,088 rev-env-{Delta}nef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in [~]38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1{micro}g/ml) and resistant viruses (IC80>3{micro}g/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01. SignificanceThis work advances our understanding of the diversity of initial viral infection and evolution and in vivo activity of broadly neutralizing antibodies (bNAbs). Deep sequencing revealed [~]38% of HIV acquisitions with multiple transmitted founder lineages, higher than previous studies. These occurrences were similar in the placebo and VRC01 groups. Viral recombination among post-acquisition variants was common under antibody selection and appeared to favor resistant sequences in the treatment group. These data suggest as with single antiviral therapy, passive and active immunization of bNAbs should be directed at multiple antigen targets of HIV-1.

molecular biology↗

bioRxiv2019

Rapid and independent evolution of ancestral and novel defenses in a genus of toxic plants (Erysimum, Brassicaceae)

Phytochemical diversity is thought to result from coevolutionary cycles as specialization in herbivores imposes diversifying selection on plant chemical defenses. Plants in the speciose genus Erysimum (Brassicaceae) produce both ancestral glucosinolates and evolutionarily novel cardenolides as defenses. Here we test macroevolutionary hypotheses on co-expression, co-regulation, and diversification of these potentially redundant defenses across this genus. We sequenced and assembled the genome of E. cheiranthoides and foliar transcriptomes of 47 additional Erysimum species to construct a highly resolved phylogeny, revealing that cardenolide diversity increased rapidly rather than gradually over evolutionary time. Concentrations, inducibility, and diversity of the two defenses varied independently among species, with no evidence for trade-offs. Closely related species shared similar cardenolide traits, but not glucosinolate traits, likely as a result of specific selective pressures acting on distinct molecular diversification mechanisms. Ancestral and novel chemical defenses in Erysimum thus appear to provide complementary rather than redundant functions.

plant biology↗

bioRxiv2019

Replicated Umbilical Cord Blood DNA Methylation Loci Associated with Gestational Age at Birth

BackgroundDNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The fetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behavior of individual genes.\n\nObjectivesThe aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in matched specimens.\n\nResultsGenome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450K BeadChip, was associated with GA for 2,372 CpG probes (5% false discovery rate) in both the Pregnancy, Race, Environment, Genes (PREG - Virginia Commonwealth University) and Newborn Epigenetic Study (NEST - Duke University) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. This assessment provides a strong evidence to support the importance of DNAm change throughout the gestational time period.\n\nConclusionsThese results converge on support for the role of variation in DNAm measures as an important genetic regulatory mechanism contributing to inter-individual differences in gestational age at birth. In particular, the pathways described are consistent with the well-known hypothesis of pathogen detection and response by the immune system to elicit premature labor as a consequence of unscheduled inflammation.

genomics↗