Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis.

Decreased HIV-specific CD8(+) T cell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8(+) T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8(+) T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8(+) T cells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. In vitro necroptosis blockade rescued HIV-specific CD8(+) T cell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8(+) T cell proliferation through activation of necroptosis and increased cell death.

Blood Pressure Goals: Is Cerebral Saturation the New Mean Arterial Pressure?

OBJECTIVE: The objective of this article was to correlate hypotension and cerebral saturation from near-infrared spectroscopy (cNIRS) in neonates on dopamine. STUDY DESIGN: Retrospective review of neonates receiving dopamine between August 2018 and 2019 was performed. Hypotension thresholds included mean arterial pressure (MAP) of postmenstrual age (PMA) ± 5 and 30 mm Hg and gestational age (GA) ± 5 mm Hg. Time below threshold MAP was compared with time with cerebral hypoxia (cNIRS <55%). RESULTS: Hypotension occurred 6 to 33% of the time on dopamine in 59 cases. Hypotension did not correlate with abnormal cNIRS overall, within PMA subgroups or by outcomes. Hypotensive periods with MAP < GA had fewer corresponding percent time with abnormal cNIRS events (3.7 ± 1.3%) compared with MAP < PMA (11.9 ± 4.9%, p < 0.003) or 30 mm Hg thresholds (12.2 ± 4.7%, p < 0.0001). In most premature infants, mean cNIRS values during hypotension were still within normal range (57 ± 6%). CONCLUSION: cNIRS may be a more clinically relevant measure than MAP for the assessment of neonatal hypotension. KEY POINTS: · Hypotension occurred 6 to 33% of the time on dopamine in 59 cases.. · Hypotension did not correlate with abnormal cNIRS overall, within PMA subgroups or by outcomes.. · MAP. · We found no cNIRS difference between IVH grades, mortality, average Hct, lactates, or urine output.. · cNIRS may be a more clinically relevant measure than MAP for the assessment of neonatal hypotension..

Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection.

Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-α, IFN-ß, myxovirus resistance protein A (MxA), human TRIM5α (huTRIM5α), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants. Samples were available for 32 uninfected subjects and 28 infected persons, all within 1 year of infection. HIV-1-positive participants had higher levels of IFN-ß (P = 0.0005), MxA (P = 0.007), and TRIM22 (P = 0.01) and lower levels of huTRIM5α (P < 0.001) than did HIV-1-negative participants. TRIM22 but not huTRIM5α correlated positively with type 1 IFN (IFN-α, IFN-ß, and MxA) (all P < 0.0001). In a multivariate model, increased MxA expression showed a significant positive association with viral load (P = 0.0418). Furthermore, TRIM22 but not huTRIM5α, IFN-α, IFN-ß, or MxA showed a negative correlation with plasma viral load (P = 0.0307) and a positive correlation with CD4(+) T-cell counts (P = 0.0281). In vitro studies revealed that HIV infection induced TRIM22 expression in PBMCs obtained from HIV-negative donors. Stable TRIM22 knockdown resulted in increased HIV-1 particle release and replication in Jurkat reporter cells. Collectively, these data suggest concordance between type 1 IFN and TRIM22 but not huTRIM5α expression in PBMCs and that TRIM22 likely acts as an antiviral effector in vivo.

Premature twin neonates with a Coronavirus-19 positive mother present with an unusual pattern of intestinal ischemia.

COVID-19 infection during pregnancy is associated with premature rupture of membranes, preterm delivery, and low birth weight. It has also been associated with hypercoagulability and vasculitis in certain patients. This article reports two premature twins born from a COVID-19 mother who presented with an unusual pattern of ileal ischemia and perforation within 24 hours of each other. We suggest that maternal infection with the novel coronavirus might lead to this atypical distribution of intestinal pathology.