SIV clearance from neonatal macaques following transient CCR5 depletion.

Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral reservoir" (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4 + T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation in CCR5 . Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.

Severe Acute Respiratory Syndrome Coronavirus 2 Delta Vaccine Breakthrough Transmissibility in Alachua County, Florida.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant has caused a dramatic resurgence in infections in the United Sates, raising questions regarding potential transmissibility among vaccinated individuals. METHODS: Between October 2020 and July 2021, we sequenced 4439 SARS-CoV-2 full genomes, 23% of all known infections in Alachua County, Florida, including 109 vaccine breakthrough cases. Univariate and multivariate regression analyses were conducted to evaluate associations between viral RNA burden and patient characteristics. Contact tracing and phylogenetic analysis were used to investigate direct transmissions involving vaccinated individuals. RESULTS: The majority of breakthrough sequences with lineage assignment were classified as Delta variants (74.6%) and occurred, on average, about 3 months (104 ±â€…57.5 days) after full vaccination, at the same time (June-July 2021) of Delta variant exponential spread within the county. Six Delta variant transmission pairs between fully vaccinated individuals were identified through contact tracing, 3 of which were confirmed by phylogenetic analysis. Delta breakthroughs exhibited broad viral RNA copy number values during acute infection (interquartile range, 1.2-8.64 Log copies/mL), on average 38% lower than matched unvaccinated patients (3.29-10.81 Log copies/mL, P < .00001). Nevertheless, 49% to 50% of all breakthroughs, and 56% to 60% of Delta-infected breakthroughs exhibited viral RNA levels above the transmissibility threshold (4 Log copies/mL) irrespective of time after vaccination. CONCLUSIONS: Delta infection transmissibility and general viral RNA quantification patterns in vaccinated individuals suggest limited levels of sterilizing immunity that need to be considered by public health policies. In particular, ongoing evaluation of vaccine boosters should specifically address whether extra vaccine doses curb breakthrough contribution to epidemic spread.

Blue Monday: Co-occurring Stimulant Use and HIV Persistence Predict Dysregulated Catecholamine Synthesis.

BACKGROUND: This longitudinal study examined whether co-occurring stimulant use and HIV disease processes predicted greater risk for depression via dysregulated metabolism of amino acid precursors for neurotransmitters. METHODS: In total, 110 sexual minority men (ie, gay, bisexual, and other men who have sex with men) living with HIV who had biologically confirmed recent methamphetamine use were enrolled in a randomized controlled trial. The kynurenine/tryptophan (K/T) and phenylalanine/tyrosine (P/T) ratios were measured over 15 months to index dysregulated metabolism of amino acid precursors for serotonin and catecholamines. Markers of gut-immune dysregulation such as lipopolysaccharide binding protein and soluble CD14 (sCD14), HIV persistence in immune cells (ie, proviral HIV DNA), and stimulant use were examined as predictors. These bio-behavioral measures, including the K/T and P/T ratios, were also examined as predictors of greater risk for depression over 15 months. RESULTS: Higher time-varying sCD14 levels (ß = 0.13; P = 0.04) and time-varying detectable viral loads (ß = 0.71; P < 0.001) were independent predictors of a higher K/T ratio. Time-varying reactive urine toxicology results for stimulants (ß = 0.53; P < 0.001) and greater proviral HIV DNA at baseline (ß = 0.34; P < 0.001) independently predicted an increased P/T ratio. Greater time-varying, self-reported methamphetamine use uniquely predicted higher odds of screening positive for depression (Adjusted Odds Ratio = 1.08; 95% confidence interval: 1.01 to 1.17). CONCLUSIONS: Ongoing stimulant use and HIV persistence independently predict dysregulated metabolism of amino acid precursors for catecholamines, but this did not explain amplified risk for depression.

Post-traumatic Stress Disorder, Cocaine Use, and HIV Persistence.

BACKGROUND: Post-traumatic stress disorder (PTSD) and stimulant use disorders are highly prevalent, commonly co-occur, and predict faster clinical HIV progression. However, scant research has examined if PTSD and cocaine use are associated with the HIV reservoir that persists in immune cells, lymphoid tissue, and organs of people living with HIV that are receiving effective treatment. METHOD: This cross-sectional study enrolled 48 HIV-positive persons with sustained undetectable viral load (< 20 copies/mL) in the past year to examine the associations of PTSD and recent cocaine use with two measures of HIV persistence in immune cells: (1) proviral HIV DNA and (2) cell-associated (CA)-HIV RNA. RESULTS: Greater PTSD symptoms were significantly associated with lower proviral HIV DNA (r = - 0.30, p = 0.041) but not with CA-HIV RNA. Greater severity of PTSD symptom clusters for intrusions (Standardized Beta = - 0.30, p = 0.038) and hyperarousal (Standardized Beta = - 0.30, p = 0.047) were independently associated with lower proviral HIV DNA. Although participants with recent cocaine use had a significantly shorter duration of sustained undetectable HIV viral load (19.9 versus 26.9 months; p = 0.047), cocaine use was not significantly associated with proviral HIV DNA or CA-HIV RNA. CONCLUSION: Further research is needed to examine the potentially bi-directional pathways linking PTSD symptom severity and HIV persistence.

Psychosocial Correlates of Monocyte Activation and HIV Persistence in Methamphetamine Users.

This cross-sectional study investigated the associations of psychosocial factors relevant to recovery from substance use disorders with monocyte activation and HIV persistence in a sample of 84 HIV-positive, methamphetamine-using sexual minority men with undetectable HIV viral load (<40 copies/mL). We examined if psychosocial factors were associated with decreased soluble CD14 (sCD14) and lower proviral HIV DNA. Multiple linear regression models adjusted for age, anti-retroviral therapy regimen, and CD4+ T-cell count. Time on ART was also included in models examining proviral HIV DNA. Greater self-efficacy for managing methamphetamine triggers and higher social support for abstinence were independently associated with lower sCD14. Greater social support for abstinence was also independently associated with lower proviral HIV DNA. Psychosocial factors relevant to recovery from substance use disorders are associated with lower monocyte activation and decreased proviral HIV DNA. Findings underscore the need for longitudinal research to identify plausible mechanisms linking psychosocial factors and substance use with biological processes relevant to HIV pathogenesis.

Neumonía por Pneumocystis jiroveci post inicio de tratamiento con infliximab en paciente con enfermedad de Crohn / Pneumocystis jiroveci pneumonia following infliximab therapy in patient with Crohn's disease

There are no evidence-based guidelines about prophylaxis against Pneumocystis jiroveci pneumonia in inflammatory bowel disease. We report a case of P. jiroveci pneumonia in patient with Crohn's disease receiving infliximab and methotrexate. This case emphasizes the importance of considering the possibility of this infection in inflammatory bowel disease patients treated on biological therapy.

[Pneumocystis jiroveci pneumonia following infliximab therapy in patient with Crohn's disease]. / Neumonía por Pneumocystis jiroveci post inicio de tratamiento con infliximab en paciente con enfermedad de Crohn.

There are no evidence-based guidelines about prophylaxis against Pneumocystis jiroveci pneumonia in inflammatory bowel disease. We report a case of P. jiroveci pneumonia in patient with Crohn's disease receiving infliximab and methotrexate. This case emphasizes the importance of considering the possibility of this infection in inflammatory bowel disease patients treated on biological therapy.

EphrinB3 regulates cell proliferation and survival in adult neurogenesis.

Interactions between ephrins and their receptors have been implicated in many processes during central nervous system development. In the adult, ephrins and Eph receptors have been implicated in controlling cell proliferation and neuroblast migration, although there is no direct evidence for the role of ephrinB3 in these functions. In addition, activation of Eph receptors has been shown to regulate transduction pathways important in cell cycle control as well as cell death. We show that ephrinB3 contributes to the control of cell proliferation and survival in the adult subventricular zone (SVZ). EphrinB3(-/-) mice exhibit a significant increase in dividing cells along the lateral ventricle, and altered expression of proteins involved in cell cycle regulation. Gain-of-function approach by infusing soluble ephrinB3-Fc molecules in ephrinB3(-/-) can suppress cell proliferation to wild type levels. At the same time, ephrinB3 also regulates cell survival as greater numbers of cells die in the SVZ of ephrinB3(-/-) mice. Together, our results suggest that ephrinB3 negatively regulates cell cycle progression and cell apoptosis in the adult subventricular zone.

[Prevalence of latex hypersensitivity in operating room workers of the University of Chile Clinical Hospital]. / Prevalencia de sensibilización a látex en personal de pabellones quirúrgicos del Hospital Clínico de la Universidad de Chile.

BACKGROUND: Health care workers (HCW) are a high risk group for developing natural rubber latex (NRL) hypersensitivity and allergy. Some studies showed a correlation between time and frequency of exposure to NRL gloves and hypersensitivity, but a recent meta-analysis showed no clear evidences for such assumption. AIM: To determine the prevalence of NRL hypersensitivity and allergy in a group of HCW at the University of Chile Clinical Hospital. MATERIALS AND METHODS: Ninety five HCW (aged 37+/-10 years, 59 females) were interviewed about time of exposure, atopic diseases and latex-related allergy symptoms. Different NRL extracts and seven NRL gloves brands were tested by the prick test method. RESULTS: Twenty four workers (25%, 95% CI = 16.9%-35.2%) were sensitized. No gender differences were found. No symptomatic cases were found in the sensitized group. In the workplace, six and two non sensitized subjects had respiratory symptoms or contact urticaria, respectively. Sensitivity to bananas, avocadoes, kiwi and chestnut was not significantly more common among latex sensitive individuals. No differences between sensitized and non sensitized subjects were observed for the presence of atopic diseases or the mean number of years at the workplace. The sensitization rate to NRL increased along with years of work, from 18.6% in patients working less than 10 years, to 28.1% in the group between 10 and 20 years and to 35% in those working more than 21 years (p=0.693). Sensitization was also related to the weekly hours of exposure: 1-10 hours, 17%; 11-20 hours, 23.5%; 21-30 hours, 50% and 31-40 hours, 28.5% (p=0.036). CONCLUSIONS: Sensitization increased proportionally to the years and weekly hours wearing NLR gloves. We did not find symptomatic patients in the sensitized group.

[Immunoglobulins in sepsis and septic shock]. / Inmunoglobulinas en sepsis y shock séptico.

Clinical efficacy of polyspecific immunoglobulins or monoclonal antibodies to treat patients with severe sepsis or septic shock is still under debate after several clinical trials. Only a few of them have been able to demonstrate a direct benefit to reduce mortality or this effect appears after meta-analysis. Evidence sustains that polyspecific immunoglobulin G reduces mortality in these patients, being this effect higher for IgM-enriched immunoglobulins. Best indications are postsurgical sepsis or early septic shock patients with high titers of endotoxinemia. The use of intravenous immunoglobulins is also recommended for the treatment of patients with streptococcal toxic shock, as demonstrated by the evidence obtained through case-control studies and one randomized clinical trial with a clear trend toward benefit. Evidence does not sustain a favorable impact on mortality for monoclonal antibodies directed against bacterial lypopolysaccaride, other bacterial antigens or against TNF-alpha. Furthermore, infusion of recombinant IL-1 receptor antagonist or soluble receptors for TNF-alpha that could attenuate the inflammatory response have not demonstrated utility after many clinical trials. These therapeutic tools are characterized by a high acquisition cost and adequate cost-effectiveness analysis has not been yet performed.

Estudio de la funcionalidad de las células NK en el embarazo / Functionality study of pregnancy NK cells

En los últimos años, la participación del sistema inmune innato en el desarrollo de la pre-eclampsia ha sido el objetivo de numerosos estudios. Sin embargo, el rol de las células agresoras naturales (NK) en esta patología no ha sido totalmente aclarado. Las células NK, componentes del sistema inmune innato, poseen actividad citotóxica espontánea, y secretan citoquinas tales como interferón gamma (INF-y ) y Factor de Necrosis Tumoral alfa (TNF-alfa). En el presente estudio hemos analizado la actividad funcional y el inmunofenotipo de células NK obtenidas desde sangre periférica de pacientes con pre-eclampsia, mujeres sanas embarazadas y mujeres sanas no embarazadas. Se cuantificó la actividad cititóxica usando el ensayo de liberación de51cromo. La producción de citoquinas en respuesta a activadores policlonales y el inmunofenotipo (CD3-CD16+CD56+) fueron determinados por citometría de flujo. Estos parámetros no evidenciaron diferencias significativas entre los grupos estudiados; sin embargo, en las pacientes con pre-eclampsia se observa una tendencia hacia una menor citotoxicidad y menor producción de TNF-alfa en células NK estimulada sin vitro, y una proporción aumentada del subtipo celular NK CD56-CD16+ en sangre periférica en relación con los otros dos grupos estudiados.

NK cells functionality during pregnancy. During the last few years, the role of innate immune system in development of pre-eclampsia has been the focus of a number of studies. However, the role of natural killer (NK) cells in pregnancy and pre-eclampsia has not been totally clarified. NK cells, an important component of innate immune system, normally exhibit spontaneus cytolytic activity and secrete cytokines such as interferon gamma (IFN-y) and tumor necrosis factor alpha (TNF-alpha). In current paper, we studied functional activity and immunophenotype of peripheral blood NKcells obtained from patients with pre-eclampsia, healthy pregnant women and non-pregnant healthy women. For this purpose, we quantified cytolytic activity using 51chromium release assay. We determined cytokine production in response to polyclonal activators and cells immunophenotype (CD3-CD16+CD56+) by flow cytometry. We found no significant differences in these parameters among the three groups studied, however, in patients with pre-eclampsia, there is a tendency to a decreased cytotoxic activity and less production of TNF-alpha by NK cells in vitro as well as an increased proportion of the NK subset CD56-CD16+, in peripheral blood.