Biology subjects

Jones, B. R.

Publications and source records attributed to Jones, B. R..

7 recordsLinked to original sources

bioRxiv2025

SARS-CoV-2 infection disrupts syncytial and endothelial integrity and alters PLGF levels in the placenta

IntroductionSARS-CoV-2 infection during pregnancy has been associated with an increased risk for several pregnancy-related disorders, particularly preeclampsia (PE). However, there are limited studies determining the impact of SARS-CoV-2 on placental physiology and function. MethodsPlacental samples were acquired from two large prospective cohorts: STOP-COVID19 and REBRACO studies. Placental villous tissues (VTs) were collected from pregnant women who tested positive for SARS-CoV-2 without PE during pregnancy. Immunohistochemistry and immunofluorescence were used to assess pathological features known to be altered in PE, including 1) syncytial knot formation; 2) alterations in renin-angiotensin system components; 3) and endothelial integrity. Maternal serum was collected to examine AT1 autoantibodies levels using an immunoassay. ResultsSARS-CoV-2 viral proteins spike, nucleocapsid, and ORF3a were observed in the syncytiotrophoblast layer and stroma of placental VT. SARS-CoV-2-infected placentas exhibited increased numbers of syncytial knots, which were positive for Flt-1 and SARS-CoV-2 viral proteins. In addition, the presence of placental infarctions and excessive fibrin deposits was also observed in infected placentas. Infection was associated with decreased placental expression of PlGF and an increase in the placental Flt-1/PlGF expression ratio, mostly driven by PlGF. No significant changes in maternal serum AT1AA levels were observed. Finally, SARS-CoV-2-infected placentas exhibited a significant decrease in vimentin expression. DiscussionSARS-CoV-2 infection negatively impacts placental integrity in the form of increased syncytial knots, dysregulated RAS components, and endothelial damage. Since all these features are similarly disrupted in PE, this could be a mechanism through which SARS-CoV-2 infection during pregnancy increases the risk of a PE-like syndrome.

microbiology↗

bioRxiv2024

Plio-Pleistocene decline of mesic forest underpins diversification in a clade of Australian Panesthia cockroaches

The progressive aridification of the Australian continent, and coincident decline of mesic forest, has been a powerful driver of allopatric and environmental speciation in native species. The relictual mesic forests of the eastern seaboard now harbor a diverse group of endemic fauna, including the wood-feeding cockroaches of the genus Panesthia, which reached the continent via two separate invasions from Melanesia. The more recent of these colonization events gave rise to a group of five recognized species, occurring in mainland woodlands, sclerophylls and rainforests, as well as the forests and grasslands of the Lord Howe Island Group. Due to limited sampling in molecular studies and doubt regarding the standing taxonomy, there is little certainty about relationships among the species and poor understanding of the effects of ancient climatic changes upon their evolution. We undertook a comprehensive phylogenetic analysis of the clade, using complete mitogenomes and nuclear ribosomal markers from nearly all known morphospecies and populations. Our time-calibrated phylogenetic analyses reveal six unrecognized, highly divergent lineages, and suggest that these have arisen primarily through vicariance as rainforests fragmented during Plio-Pleistocene glacial cycles (2-5 million years ago). Ancestral niche reconstructions also evidence a tropical rainforest origin for the group, followed by at least three niche transitions into drier forest, including one associated with the singular colonization of the Lord Howe Island Group. Finally, we find evidence of frequent, parallel wing reduction, in potential association with the contraction of forest habitats into small refugia. Our results reiterate the far-reaching role of ancient aridification in driving speciation, niche expansion and morphological evolution in Australian fauna.

evolutionary biology↗

bioRxiv2023

HIV reservoirs are dominated by genetically younger and clonally enriched proviruses

In order to cure HIV, we need to better understand the within-host evolutionary origins of the small reservoir of genome-intact proviruses that persists within infected cells during antiretroviral therapy (ART). Most prior studies on reservoir evolutionary dynamics however did not discriminate genome-intact proviruses from the vast background of defective ones. We reconstructed within-host pre-ART HIV evolutionary histories in six individuals and leveraged this information to infer the ages of intact and defective proviruses sampled after an average >9 years on ART, along with the ages of rebound and low-level/isolated viremia occurring during this time. We observed that the longest-lived proviruses persisting on ART were exclusively defective, usually due to large deletions. In contrast, intact proviruses and rebound HIV exclusively dated to the years immediately preceding ART. These observations are consistent with genome-intact proviruses having shorter lifespans, likely due to the cumulative risk of elimination following viral reactivation and protein production. Consistent with this, intact proviruses (and those with packaging signal defects) were three times more likely to be genetically identical compared to other proviral types, highlighting clonal expansion as particularly important in ensuring their survival. By contrast, low-level/isolated viremia sequences were genetically heterogeneous and sometimes ancestral, where viremia may have originated from defective proviruses. Results reveal that the HIV reservoir is dominated by clonally-enriched and genetically younger sequences that date to the untreated infection period when viral populations had been under within-host selection pressures for the longest duration. Knowledge of these qualities may help focus strategies for reservoir elimination. ImportanceCharacterizing the HIV reservoir that endures despite antiretroviral therapy (ART) is critical to cure efforts. Our observation that the oldest proviruses persisting during ART were exclusively defective, while intact proviruses (and rebound HIV) all dated to the years immediately pre- ART, explains why prior studies that sampled sub-genomic proviruses on-ART (which are largely defective) routinely found sequences dating to early infection, whereas those that sampled viral outgrowth sequences found essentially none. Together with our findings that intact proviruses were also more likely to be clonal, and that on-ART low-level/isolated viremia originated from proviruses of varying ages (including possibly defective ones), our observations indicate that: 1) on-ART and rebound viremia can have distinct within-host origins, 2) intact proviruses have shorter lifespans than grossly-defective ones, and therefore depend on clonal expansion for persistence, and 3) the HIV reservoir, being overall genetically younger, will be substantially adapted to within-host pressures, complicating immune-based cure strategies.

genetics↗

bioRxiv2023

Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

microbiology↗

bioRxiv2022

HIV proviral genetic diversity, compartmentalization and inferred dynamics in lung and blood during long-term suppressive antiretroviral therapy

The lung is an understudied site of HIV persistence. We isolated 882 subgenomic proviral sequences by single-genome approaches from blood and lung from nine individuals on long-term suppressive antiretroviral therapy (ART), and characterized genetic diversity and compartmentalization using formal tests. Consistent with clonal expansion as a driver of HIV persistence, identical sequences comprised between 9% to 86% of within-host datasets, though their location (blood vs. lung) followed no consistent pattern. The majority (77%) of participants harbored at least one sequence shared across blood and lung, supporting the migration of clonally-expanded cells between sites. No participant exhibited genetic compartmentalization so obvious that it was visually apparent in a phylogeny. When formal tests were applied however, two (22%) participants showed modest yet significant support for compartmentalization when analysis was restricted to distinct proviruses per site. This increased to four participants (44%) when considering all within-host sequences. Thus, while a minority of individuals harbor somewhat distinctive proviral populations in blood and lung, these can simply be due to unequal distributions of clonally-expanded sequences. Importantly, the extent of lung proviral diversity on ART strongly reflected that in blood (Spearman {rho} = 0.98, p < 0.0001), confirming blood as a strong indicator of total body proviral diversity. Analysis of on-ART proviral diversity in context of pre-therapy viral diversity in two participants revealed marked differences in proviral longevity and dynamics. Whereas one participants proviral pool was rich in ancestral sequences that recapitulated more of HIVs within-host evolutionary history, the others largely comprised more contemporary sequences, including ones that re-seeded the reservoir during a three-year treatment interruption. Results highlight the genetic complexity of proviruses persisting in lung and blood during ART, and the uniqueness of each individuals proviral composition. Individualized HIV remission and cure strategies may be needed to overcome these challenges. Author SummaryHIV persists in the body despite long-term suppressive antiretroviral therapy. Much of our knowledge about the HIV reservoir comes from studying proviruses in blood, but a fundamental question is whether these are distinct from those in tissues. The lung could theoretically engender genetically distinctive HIV populations, but this remains understudied. Our analysis of nearly 900 proviral sequences from blood and lung of nine individuals with HIV receiving long-term therapy revealed substantial within-host heterogeneity, yet some common patterns. Identical sequences (consistent with clonal expansion of infected cells) were observed in everyone, though at different (9-86%) frequencies. Recovery of shared sequences across blood and lung was common (77% of participants). Fewer than half of participants exhibited blood-lung genetic compartmentalization, and only modestly so. Moreover, when present, compartmentalization was often attributable to differential distribution of identical sequences, not the presence of genetically distinctive populations, across sites. Results also revealed marked inter-individual differences in proviral dynamics, as evidenced by the proportion of persisting proviruses that represented ancestral versus more recently-circulating viral sequences. Critically, the extent of within-host proviral diversity in blood correlated strongly with that in lung, indicating that despite inter-individual heterogeneity, blood is a strong indicator of proviral diversity elsewhere in the body.

molecular biology↗

bioRxiv2021

HIV proviral burden, genetic diversity and dynamics in viremic controllers who subsequently initiated suppressive antiretroviral therapy

Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding the burden, genetic diversity and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups. Among them are viremic controllers, individuals who naturally suppress HIV to low levels but for whom therapy is nevertheless recommended. We reconstructed within-host HIV evolutionary histories from longitudinal single-genome amplified viral sequences in four viremic controllers who eventually initiated ART, and used this information to characterize the age and diversity of proviruses persisting on therapy. We further leveraged these within-host proviral age distributions to estimate rates of proviral turnover prior to ART. This is an important yet understudied metric, since pre-ART proviral turnover dictates reservoir composition at ART initiation (and thereafter), which is when curative interventions, once developed, would be administered. Despite natural viremic control, all participants displayed significant within-host HIV evolution pre-therapy, where overall on-ART proviral burden and diversity broadly reflected the extent of viral replication and diversity pre-ART. Consistent with recent studies of non-controllers, the proviral pools of two participants were skewed towards sequences that integrated near ART initiation, suggesting dynamic proviral turnover during untreated infection. In contrast, proviruses recovered from the two other participants dated to time-points that were more evenly spread throughout infection, suggesting slow or negligible proviral decay following deposition. HIV cure strategies will need to overcome within-host proviral diversity, even in individuals who naturally controlled HIV replication before therapy. ImportanceHIV therapy is life-long because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure. Elite controllers, individuals who naturally suppress HIV to undetectable levels, are being intensely studied as models of HIV remission, but viremic controllers, individuals who naturally suppress HIV to low levels, remain understudied even though they too may hold valuable insights. We combined phylogenetics and mathematical modeling to reconstruct proviral seeding and decay from infection to therapy-mediated suppression in four viremic controllers. We recovered diverse proviruses persisting during therapy that broadly reflected HIVs within-host evolutionary history, where the estimated half-lives of the persistent proviral pool during untreated infection ranged from <1 year to negligible. Cure strategies will need to contend with proviral diversity and between-host heterogeneity, even in individuals who naturally control HIV.

microbiology↗

bioRxiv2018

Tree Shape-based approaches for the Comparative study of Cophylogeny

Cophylogeny is the congruence of phylogenetic relationships between two different groups of organisms due to their long-term interaction, such as between host and pathogen species. Discordance between host and pathogen phylogenies may occur due to pathogen host-switch events, pathogen speciation within a host species, and extinction. Here, we investigated the use of tree shape distance measures to quantify the degree of cophylogeny for the comparative analysis of host-pathogen interactions across taxonomic groups.\n\nWe firstly implemented a coalescent model to simulate pathogen phylogenies within a fixed host tree, given the cospeciation probability, migration rate between hosts, and pathogen speciation rate within hosts.\n\nNext, we used simulations from this model to evaluate 13 distance metrics between these trees and the host tree, including Robinson-Foulds distance and two kernel distances that we developed for labeled and unlabeled trees, which use branch lengths and can accommodate trees of different sizes. Finally, we used these distance metrics to revisit actual datasets from published cophylogenetic studies across all taxonomic groups, where authors described the observed associations as representing a high or low degree of cophylogeny.\n\nOur simulation analyses demonstrated that some metrics are more informative than others with respect to specific coevolution parameters. For example, the Sim metric was the most responsive to variation in coalescence rates, whereas the unlabeled kernel metric was the most responsive to cospeciation probabilities. We also determined that distance metrics were more informative about the model parameters when the underlying parameter values did not assume extreme values, e.g., rapid host switching. When applied to real datasets, projection of these trees associations into a parameter space defined by the 13 distance metrics revealed some clustering of studies reporting low concordance. This suggested that different investigators are describing concordance in a consistent way across biological systems, and that these expert subjective assessments can be at least partly quantified using distance metrics.\n\nOur results support the hypothesis that tree distance measures can be useful for quantifying host and pathogen cophylogeny. This motivates the usage of distance metrics in the field of coevolution and supports the development of simulation-based methods, i.e., approximate Bayesian computation, to estimate coevolutionary parameters from the discordant shapes of host and pathogen trees. [tree shape; cophylogeny; codivergence; coevolution; host switching; tree metrics; kernel]

evolutionary biology↗