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.

The Breadth of Expandable Memory CD8+ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers.

UNLABELLED: Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8(+) T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P = 0.01) as well as treated progressors (P = 0.0003). Nef- and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P = 0.9 for Nef as determined by a Kruskal-Wallis test; P = 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r = -0.6; P = 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8(+) T cell feature that would be desirable in a vaccine-induced T cell response. IMPORTANCE: Many studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8(+) T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8(+) T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8(+) T cell responses.

Current Practices Supporting Rigid Bronchoscopy-An International Survey.

BACKGROUND: There are no guidelines for anesthesia or staff support needed during rigid bronchoscopy (RB). Identifying current practice patterns for RB pertinent to anesthesia, multidisciplinary teams, and algorithms of intra and post-procedural care may inform best practice recommendations. METHODS: Thirty-three-question survey created obtaining practice patterns for RB, disseminated via email to the members of the American Association of Bronchology and Interventional Pulmonology and the American College of Chest Physicians Interventional Chest Diagnostic Procedures Network. RESULTS: One hundred seventy-five clinicians participated. Presence of a dedicated interventional pulmonology (IP) suite correlated with having a dedicated multidisciplinary RB team ( P =0.0001) and predicted higher likelihood of implementing team-based algorithms for managing complications (39.4% vs. 23.5%, P =0.024). A dedicated anesthesiology team was associated with the increased use of high-frequency jet ventilation ( P =0.0033), higher likelihood of laryngeal mask airway use post-RB extubation ( P =0.0249), and perceived lower rates of postprocedural anesthesia adverse effects ( P =0.0170). Although total intravenous anesthesia was the most used technique during RB (94.29%), significant variability in the modes of ventilation and administration of muscle relaxants was reported. Higher comfort levels in performing RB are reported for both anesthesiologists ( P =0.0074) and interventional pulmonologists ( P =0.05) with the presence of dedicated anesthesia and RB supportive teams, respectively. CONCLUSION: Interventional bronchoscopists value dedicated services supporting RB. Multidisciplinary dedicated RB teams are more likely to implement protocols guiding management of intraprocedural complications. There are no preferred modes of ventilation during RB. These findings may guide future research on RB practices.

Safety and Efficacy of Manual Aspiration Via Small Bore Chest Tube in Facilitating the Outpatient Management of Transbronchial Biopsy-related Iatrogenic Pneumothorax.

BACKGROUND: Iatrogenic pneumothorax complicates transbronchial biopsies with a prevalence of 1% to 6%. Conventional treatment consists of inpatient management with chest tube drainage. While aspiration techniques have been investigated in the management of both primary spontaneous and transthoracic lung biopsy-induced pneumothorax, its role in the management of transbronchial biopsy-iatrogenic pneumothorax (TBBX-IP) is undefined. An appealing treatment alternative for TBBX-IP may exist in the placement of a small bore chest tube (SBCT) followed by a manual aspiration (MA) technique promoting earlier SBCT removal to facilitate outpatient management. To our knowledge, no study exists evaluating the efficacy of MA via a SBCT performed specifically for TBBX-IP. PATIENTS AND METHODS: Prospective evaluation of the efficacy of a protocolized pathway incorporating MA through a SBCT for the outpatient management of TBBX-IP. Primary outcome was the clinicoradiographic resolution of TBBX-IP avoiding hospitalizations. RESULTS: A total of 763 biopsies performed; 31 complicated by TBBX-IP, 18 qualified for intervention. Sixteen were outpatients, 2 inpatients. Thirteen (81.25%) of the 16 outpatients were successfully treated with MA via SBCT and did not require admission. Twelve (75%) of these 13 had SBCT removed, 1 patient was discharged with SBCT and removed in 24 hours. Of the 18 patients requiring intervention, 13 (72.2%) were successfully treated with MA via SBCT enabling removal of SBCT. No patient required reintervention. CONCLUSION: MA via SBCT represents a safe and viable management approach of TBBX-IP promoting earlier SBCT removal and decreased hospitalizations. Our results challenge conventional management of TBBX-IP warranting further investigation.