HIV-1-infected cells persist indefinitely despite the use of combination antiretroviral therapy (ART), and novel therapeutic strategies to target and purge residual infected cells in individuals on ...ART are urgently needed. Here, we demonstrate that CD4+ T cell-associated HIV-1 RNA is often highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4+ lymphocytes in individuals on suppressive ART. Using in situ RNA hybridization studies, we show co-localization of CD30 with HIV-1 transcriptional activity in gut-associated lymphoid tissues. We also demonstrate that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. Finally, we observed that an HIV-1-infected individual, who received repeated brentuximab vedotin infusions for lymphoma, had no detectable virus in peripheral blood mononuclear cells. Overall, CD30 may be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART. Given that CD30 is only expressed on a small number of total mononuclear cells, it is a potential therapeutic target of persistent HIV-1 infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human Herpes Virus 8 (HHV8) can cause Kaposi's Sarcoma (KS) in immunosuppressed individuals. However, little is known about the association between chemotherapy or hematopoietic stem cell ...transplantation (HSCT), circulating HHV8 DNA levels, and clinical KS in HIV-1-infected individuals with various malignancies. Therefore, we examined the associations between various malignancies, systemic cancer chemotherapy, T cell phenotypes, and circulating HHV8 DNA in 29 HIV-1-infected participants with concomitant KS or other cancer diagnoses.
We quantified HHV8 plasma viral loads and cell-associated HHV8 DNA and determined the relationship between circulating HHV8 DNA and lymphocyte counts, and markers of early and late lymphocyte activation, proliferation and exhaustion.
There were no significant differences in plasma HHV8 DNA levels between baseline and post-chemotherapy time points or with the presence or absence of clinical KS. However, in two participants circulating HHV8 DNA increased following treatment for KS or HSCT for lymphoma,. We observed an approximately 2-log10 reduction in plasma HHV8 DNA in an individual with KS and multicentric Castleman disease following rituximab monotherapy. Although individuals with clinical KS had lower mean CD4+ T cell counts and percentages as expected, there were no significant associations with these factors and plasma HHV8 levels. We identified increased proportions of CD8+ and CD4+ T cells expressing CD69 (P = 0.01 & P = 0.04 respectively), and increased CD57 expression on CD4+ T cells (P = 0.003) in participants with detectable HHV8.
These results suggest there is a complex relationship between circulating HHV8 DNA and tissue-based disease in HIV-1 and HHV8 co-infected individuals with various malignancies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Assays that can verify full viral eradication are essential in the context of achieving a cure for HIV/AIDS. In vitro quantitative viral out growth assays (qVOA) are currently the gold ...standard for measuring latent HIV-1 but these assays often fail to detect very low levels of replication-competent virus. Here we investigated an alternative in vivo approach for sensitive viral detection using humanized mice (hmVOA). Peripheral blood CD4+ T cell samples from HIV subjects on stable ART with undetectable viral loads by RT-PCR were first assayed by in vitro qVOA. Corresponding patient samples in which no virus was detected by qVOA were injected into humanized mice to allow viral outgrowth. Of the five qVOA virus negative samples, four gave positive viral outgrowth in the hmVOA assay suggesting that it is more sensitive in detecting latent HIV-1.
Cracks can form in silicon solar cells in an otherwise intact photovoltaic module due to mechanical stresses such as rough handling or hail. The immediate impact on power due to these cracks can be ...readily measured, but it is also known from accelerated testing that the cracks can worsen over time. However, it is not clear how to predict the extent of future field degradation due to cracked cells, which requires a calibrated accelerated test. We describe progress toward such a test. In particular, we report on the outdoor aging of modules with cracked cells for nearly two years. We find that modules with cracked cells degraded in the field an average of 0.5% absolute more than uncracked modules over a period of 21 months. We also characterize the modules with multitemperature electroluminescence and find that the degradation is associated with cell fragments that become electrically isolated. We compare the weathering outdoors with the two types of accelerated tests: thermal cycling and a novel accelerated test, dynamic mechanical acceleration (DMX). DMX can apply thousands of pressure cycles at a frequency of approximately 10 Hz and pressures <200 Pa, which are relevant to the wind-driven pressure cycles experienced by modules outdoors. We find that the thermal cycles designed to reproduce the cumulative temperature change from the field overestimate field degradation and can excite noncell-crack degradation. DMX results were promising, reproducing degradation levels similar to those observed outdoors over 21 months with a test that can be performed in less than an hour.
Range shifts as a result of warming oceans call for evaluation of populations at the geographic range level, particularly for highly vulnerable species such as endemics and fisheries targets. We ...examined the influence of latitudinal temperature gradients and temperature anomalies during a 2011 marine heat wave on range-wide abundance, length frequency and recruitment of
Choerodon rubescens
, a reef associated fisheries target endemic to Western Australia. Diver-operated stereo-video surveys were conducted at shallow reefs (3–18 m) along 124 sites spanning the entire species’ distribution (21°S–34°S), to obtain abundance, length frequency and habitat data. Models were used to assess the influence of satellite-derived long-term average temperature (2002–2010) and 2011 temperature anomalies, compared to habitat, depth and distance to mainland, on the abundance of adult and juvenile fish and overall population size structure. Long-term temperature had the highest effect on adult
C. rubescens
abundance, with highest values recorded towards the centre of the temperature gradient investigated (22 °C). In contrast, juveniles were mostly influenced by 2011 temperature anomalies, with highest abundance recorded towards the cooler range edge, where anomalies were lowest. Length-frequency distributions showed recent recruitment towards the cooler range edge coupled with recruitment absence at the warmer edge. Recruitment differences were traced to 2011–2013 when ocean temperatures were up to 3.5 °C higher than average, via back-calculation of juvenile ages. These findings support predictions of a poleward distributional shift in response to ocean warming, and suggest that marine heatwaves can facilitate range shifts by affecting recruitment across latitudinal gradients.
The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host ...genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA tDNA, unspliced RNA usRNA, intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. While the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of ...PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Here, using knockin (KI) mice harboring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. Thus, we find that the dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN loss-driven cancers.
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•Loss of PTEN function cooperates with oncogenic PIK3CA in mammary tumorigenesis•Targeted AKT inhibition suppresses growth of PTEN and PI3K mutant mammary organoids•Loss of PTEN protein-phosphatase activity sensitizes tumors and cells to death•GR mediates the failsafe mechanism driven by loss of PTEN protein function
Yip et al. demonstrate that loss of the tumor suppressor PTEN synergizes with mutant PI3K in mammary tumorigenesis but also renders tumor cells sensitive to death induced by the glucocorticoid receptor (GR). The authors conclude that GR action and AKT inhibition can provide a new treatment for PTEN/PI3K mutant cancers.
Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of ...detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients’ homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE²RD), which addresses all these impediments on a single platform. The NE²RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE²RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE²RD’s broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the pointof-care or primary care settings and at patients’ homes.
Background. Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency ...virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses. Methods. We investigated the changes in peripheral CD4+ T-cell–associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1–infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors. Results. Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell–associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)– and Epstein-Barr virus (EBV)–responsive CD4+ T cells following chemotherapy. Conclusions. Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy.
Abstract
We present the current state of models for the
z
∼ 3 carbon monoxide (CO) line intensity signal targeted by the CO Mapping Array Project (COMAP) Pathfinder in the context of its early ...science results. Our fiducial model, relating dark matter halo properties to CO luminosities, informs parameter priors with empirical models of the galaxy–halo connection and previous CO (1–0) observations. The Pathfinder early science data spanning wavenumbers
k
= 0.051–0.62 Mpc
−1
represent the first direct 3D constraint on the clustering component of the CO (1–0) power spectrum. Our 95% upper limit on the redshift-space clustering amplitude
A
clust
≲ 70
μ
K
2
greatly improves on the indirect upper limit of 420
μ
K
2
reported from the CO Power Spectrum Survey (COPSS) measurement at
k
∼ 1 Mpc
−1
. The COMAP limit excludes a subset of models from previous literature and constrains interpretation of the COPSS results, demonstrating the complementary nature of COMAP and interferometric CO surveys. Using line bias expectations from our priors, we also constrain the squared mean line intensity–bias product,
Tb
2
≲ 50
μ
K
2
, and the cosmic molecular gas density,
ρ
H2
< 2.5 × 10
8
M
⊙
Mpc
−3
(95% upper limits). Based on early instrument performance and our current CO signal estimates, we forecast that the 5 yr Pathfinder campaign will detect the CO power spectrum with overall signal-to-noise ratio of 9–17. Between then and now, we also expect to detect the CO–galaxy cross-spectrum using overlapping galaxy survey data, enabling enhanced inferences of cosmic star formation and galaxy evolution history.
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