The diagnosis of postacute sequelae of coronavirus disease 2019 (PASC) poses an ongoing medical challenge. To identify biomarkers associated with PASC we analyzed plasma samples collected from PASC ...and coronavirus disease 2019 patients to quantify viral antigens and inflammatory markers. We detect severe acute respiratory syndrome coronavirus 2 spike predominantly in PASC patients up to 12 months after diagnosis.
With more than 38 million people living with HIV-1 (PLWH) worldwide, developing a cure for HIV-1 remains a major global health priority. Lifelong persistence of HIV-1 is frequently attributed to a ...pool of stable, transcriptionally silent HIV-1 proviruses, which are unaffected by currently available antiretroviral therapy (ART) or host immune activity. In this opinion article, we propose a more dynamic interpretation of HIV-1 reservoir cell biology and argue that HIV-1 proviruses frequently display residual viral transcriptional activity, making them vulnerable to longitudinal immune-mediated selection processes. Such mechanisms may, over extended periods of ART, induce an attenuated viral reservoir profile characterized by intact proviruses preferentially integrated into heterochromatin locations. We suggest that intensifying and accelerating naturally occurring selection mechanisms might represent a promising strategy for finding a potential cure for HIV-1 infection.
Dendritic cells (DCs) are professional antigen-presenting cells that link innate and adaptive immunity and are critical for the induction of protective immune responses against pathogens. Proportions ...of these cells are markedly decreased in the blood of untreated HIV-1-infected individuals, suggesting they might be intrinsically involved in HIV-1 pathogenesis. However, despite several decades of active research, the precise role and contribution of these cells to protective or detrimental host responses against HIV-1 are still remarkably unclear. Recent studies have shown that DCs possess a fine-tuned machinery to recognize HIV-1 replication products through a variety of innate pathogen sensing mechanisms, which may be instrumental for generating both cellular and humoral protective immune responses in persons who naturally control HIV-1 replication. Yet, dysregulated and abnormal activation of DCs might also contribute to sustained inflammation and immune activation accelerating disease progression during chronic progressive infection. Emerging data also suggest that DCs can influence the induction of potent broadly-neutralizing antibodies, and may, for this reason, have to be considered as important components of future HIV-1 vaccination strategies. Apart from their involvement in antiviral host immunity, at least a subgroup of DCs seem intrinsically susceptible to HIV-1 infection and may serve as a viral target cell population. Indeed recent studies suggest that specific DC subpopulations residing in the genital mucosa are preferentially infected by HIV-1 and play an active role in sexual transmission; therefore, DCs may contribute to viral dissemination and possible persistence of the viral reservoirs through either direct or indirect mechanisms. Here, we analyze the distinct and partially opposing roles of DCs during HIV-1 disease pathogenesis, with a focus on implications of DC biology natural immune control and HIV cure research efforts.
This letter describes an immunocompromised patient who had persistent infection with SARS-CoV-2 over a period of months, despite several courses of remdesivir. Phylogenetic analysis showed ...accelerated viral evolution.
As schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is ...critical.
Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified.
A total of 192 children (mean age, 10.2 ± 7.0 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met the criteria for MIS-C. Only 25 children (51%) with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were nonspecific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower angiotensin-converting enzyme 2 expression (P = .004). Immunoglobulin M (IgM) and Immunoglobulin G (IgG) to the receptor binding domain of the SARS-CoV-2 spike protein were increased in severe MIS-C (P < .001), with dysregulated humoral responses observed.
This study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic despite having milder disease or a lack of symptoms; immune dysregulation is implicated in severe postinfectious MIS-C.
HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered “transcriptionally silent,” but active viral gene expression may occur in some cells, challenging the ...concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.
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•A multidimensional assay for HIV-1 reservoir cell profiling is presented (PRIP-seq)•Transcriptionally active HIV-1 proviruses are actively selected against during ART•Large transcriptionally active proviral clones resist negative host selection forces•Epigenetic signals in linear and 3D chromatin contacts influence HIV-1 transcription
PRIP-seq is a multidimensional single-cell assay that simultaneously captures the proviral sequence, the corresponding chromosomal integration site, and the expression of HIV-1 RNA in single virally infected cells and allows for the global mapping of transcriptionally active and silent proviruses in patients receiving suppressive antiretroviral therapy.
Untreated HIV-1 infection typically progresses to AIDS within 10 years, but less than 1% of infected individuals remain healthy and have normal CD4(+) T cell counts and undetectable viral loads; some ...individuals have remained this way for 35 years and counting. Through a combination of large population studies of cohorts of these 'HIV-1 controllers' and detailed studies of individual patients, a heterogeneous picture has emerged regarding the basis for this remarkable resistance to AIDS progression. In this Review, we highlight the host genetic factors, the viral genetic factors and the immunological factors that are associated with the controller phenotype, we discuss emerging methodological approaches that could facilitate a better understanding of spontaneous HIV-1 immune control in the future, and we delineate implications for a 'functional cure' of HIV-1 infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose of review
HIV-1 elite controllers encompass small populations of people infected with HIV-1 who can spontaneously control plasma viral loads below the limit of detection, in the absence of ...antiretroviral treatment. Antiviral immune responses are likely to contribute to such an impressive HIV-1 disease outcome. In this review, we discuss recent novel findings regarding antiviral innate and adaptive immune responses in elite controllers.
Recent findings
Elite controllers maintain a pool of infected cells in which intact HIV-1 proviruses are more frequently integrated into noncoding regions of the host genome, likely conferring a state of deep latency. This atypical viral reservoir configuration is best explained by potent antiviral immune responses that can successfully eliminate virally infected cells in which proviruses are integrated into permissive chromatin. However, identifying the specific type and nature of this immune selection pressure represents a formidable challenge. Recent studies continue to support the role of HIV-1-specific CD8
+
T cells as the main driver of elite immune control of HIV-1, however, increasing evidence suggests that their role is complemented by a fine-tuned interplay with innate immune cell subsets. Therefore, the combination of different immune effector mechanisms may shape antiviral immunity in elite controllers.
Summary
Understanding the complex immune mechanisms responsible for natural, drug-free HIV-1 control represents a premier avenue to find and develop interventions for a cure of HIV-1 infection. Future single-cell assays designed to uncover the full genetic, epigenetic, transcriptional and functional complexity of antiviral immune responses in elite controllers may allow us to define correlates of antiviral immune protection in greater detail.
Biological data are lacking with respect to risk of vertical transmission and mechanisms of fetoplacental protection in maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...infection.
To quantify SARS-CoV-2 viral load in maternal and neonatal biofluids, transplacental passage of anti-SARS-CoV-2 antibody, and incidence of fetoplacental infection.
This cohort study was conducted among pregnant women presenting for care at 3 tertiary care centers in Boston, Massachusetts. Women with reverse transcription-polymerase chain reaction (RT-PCR) results positive for SARS-CoV-2 were recruited from April 2 to June 13, 2020, and follow-up occurred through July 10, 2020. Contemporaneous participants without SARS-CoV-2 infection were enrolled as a convenience sample from pregnant women with RT-PCR results negative for SARS-CoV-2.
SARS-CoV-2 infection in pregnancy, defined by nasopharyngeal swab RT-PCR.
The main outcomes were SARS-CoV-2 viral load in maternal plasma or respiratory fluids and umbilical cord plasma, quantification of anti-SARS-CoV-2 antibodies in maternal and cord plasma, and presence of SARS-CoV-2 RNA in the placenta.
Among 127 pregnant women enrolled, 64 with RT-PCR results positive for SARS-CoV-2 (mean SD age, 31.6 5.6 years) and 63 with RT-PCR results negative for SARS-CoV-2 (mean SD age, 33.9 5.4 years) provided samples for analysis. Of women with SARS-CoV-2 infection, 23 (36%) were asymptomatic, 22 (34%) had mild disease, 7 (11%) had moderate disease, 10 (16%) had severe disease, and 2 (3%) had critical disease. In viral load analyses among 107 women, there was no detectable viremia in maternal or cord blood and no evidence of vertical transmission. Among 77 neonates tested in whom SARS-CoV-2 antibodies were quantified in cord blood, 1 had detectable immunoglobuilin M to nucleocapsid. Among 88 placentas tested, SARS-CoV-2 RNA was not detected in any. In antibody analyses among 37 women with SARS-CoV-2 infection, anti-receptor binding domain immunoglobin G was detected in 24 women (65%) and anti-nucleocapsid was detected in 26 women (70%). Mother-to-neonate transfer of anti-SARS-CoV-2 antibodies was significantly lower than transfer of anti-influenza hemagglutinin A antibodies (mean SD cord-to-maternal ratio: anti-receptor binding domain immunoglobin G, 0.72 0.57; anti-nucleocapsid, 0.74 0.44; anti-influenza, 1.44 0.80; P < .001). Nonoverlapping placental expression of SARS-CoV-2 receptors angiotensin-converting enzyme 2 and transmembrane serine protease 2 was noted.
In this cohort study, there was no evidence of placental infection or definitive vertical transmission of SARS-CoV-2. Transplacental transfer of anti-SARS-CoV-2 antibodies was inefficient. Lack of viremia and reduced coexpression and colocalization of placental angiotensin-converting enzyme 2 and transmembrane serine protease 2 may serve as protective mechanisms against vertical transmission.
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem ...thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific “disease-related” B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
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•Germinal centers are lost in lymph nodes and spleens in acute COVID-19•Bcl-6+ GC B cells and Bcl-6+ T follicular helper cells are markedly diminished•Abundant TH1 cells and aberrant TNF-α production are seen in COVID-19 lymph nodes•SARS-CoV-2-specific activated B cells accumulate in the blood of patients
Shiv Pillai and colleagues show that in acute COVID-19, there is a striking loss of germinal centers in lymph nodes and spleens and depletion of Bcl-6+ B cells but preservation of AID+ B cells. A specific block in germinal center type Bcl-6+ T follicular helper cell differentiation may explain the loss of germinal centers and the accumulation of non-germinal-center-derived activated B cells. These data suggest an underlying basis for the lower quality and lack of durability of humoral immune responses observed during natural infection with SARS-CoV-2 and have significant implications for expectations of herd immunity.
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