Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses.

Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections.

African green monkeys (AGM) and sooty mangabeys (SM) are well-studied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent studies have shown that CCR5 is dispensable for SIV infection of SM in vivo and that blocking of CCR5 does not prevent ex vivo infection of peripheral blood mononuclear cells (PBMC) from SM or vervet AGM. In both hosts, CXCR6 is an efficient entry pathway in vitro Here we investigated the use of species-matched CXCR6 and other alternative coreceptors by SIVagmSab, which infects sabaeus AGM. We cloned sabaeus CD4 and 10 candidate coreceptors. Species-matched CXCR6, CCR5, and GPR15 mediated robust entry into transfected cells by pseudotypes carrying SIVagmSab92018ivTF Env, with lower-level entry through GPR1 and APJ. We cloned genetically divergent env genes from the plasma of two wild-infected sabaeus AGM and found similar patterns of coreceptor use. Titration experiments showed that CXCR6 and CCR5 were more efficient than other coreceptors when tested at limiting CD4/coreceptor levels. Finally, blocking of CXCR6 with its ligand CXCL16 significantly inhibited SIVagmSab replication in sabaeus PBMC and had a greater impact than did the CCR5 blocker maraviroc, confirming the use of CXCR6 in primary lymphocyte infection. These data suggest a new paradigm for SIV infection of natural host species, whereby a shared outcome of virus-host coevolution is the use of CXCR6 or other alternative coreceptors for entry, which may direct SIV toward CD4+ T cell subsets and anatomical sites that support viral replication without disrupting immune homeostasis and function. IMPORTANCE: Natural hosts of SIV do not progress to AIDS, in stark contrast to pathogenic human immunodeficiency virus type 1 (HIV-1)-human and SIVmac-macaque infections. Identifying how natural hosts avoid immunodeficiency can elucidate key mechanisms of pathogenesis. It is known that despite high viral loads, natural hosts have a low frequency of CD4+ cells expressing the SIV coreceptor CCR5. In this study, we demonstrate the efficient use of the coreceptor CXCR6 by SIVagmSab to infect sabaeus African green monkey lymphocytes. In conjunction with studies of SIVsmm, which infects sooty mangabeys, and SIVagmVer, which infects vervet monkeys, our data suggest a unifying model whereby in natural hosts, in which the CCR5 expression level is low, the use of CXCR6 or other coreceptors to mediate infection may target SIV toward distinct cell populations that are able to support high-level viral replication without causing a loss of CD4+ T cell homeostasis and lymphoid tissue damage that lead to AIDS in HIV-1 and SIVmac infections.

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV.

UNLABELLED: Natural-host sooty mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4(+) T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4(+) T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIVsmm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4(+) T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4(+) T cell loss. IMPORTANCE: Natural hosts of SIV, such as sooty mangabeys, sustain high viral loads but do not develop disease, while nonnatural hosts, like rhesus macaques, develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5, suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that in sooty mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may redirect the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of nonessential cells and limit infection of critical cells in natural hosts, thus contributing to benign outcome of infection.

Venous Thromboembolism in Children and Teenagers Admitted for Trauma: A 5-Year Nationwide Perspective.

Venous thromboembolism (VTE) in pediatric trauma patients is under-investigated. The purpose of this study was to perform an evaluation of the risk factors for VTE after pediatric trauma, including readmissions across the United States. The Nationwide Readmissions Database for 2016-2020 was queried for all patients under the age of 18 years admitted for trauma. 276 670 patients were identified; 2063 (.8%) were diagnosed with VTE. Among those with VTE, 300 (15%) were identified during a readmission. Higher rates of VTE were seen in ages 15-17 years (n = 1,294, 1.3%, P < .001), penetrating injuries (n = 478, .9%, P < .001), and assault (n = 271, 2.7%, P < .001). The strongest risk factor for VTE was prolonged mechanical ventilation (OR 5.5 [4.9-6.3] P < .001). Our study found that a significant portion of post-traumatic VTE in children and teenagers occur during readmissions. A deeper understanding of the risk factors outlined here can guide enhanced clinical protocols, ensuring early detection and prevention of this complication.

Surgical Urgency, Patient Comorbidities, and Socioeconomic Factors in Surgical Site Infections in Pediatric Surgery.

BACKGROUND: The rise of value-based purchasing has led to decreased compensation for hospital-acquired conditions, including surgical site infections (SSI). This study aims to assess the risk factors for SSI in children and teenagers undergoing gastrointestinal surgery across US hospitals. METHODS: The 2018-2020 Nationwide Readmissions Database was queried for patients undergoing gastrointestinal surgery under the age of 18. The primary outcome was SSI during index admission or readmission within a year. Comparison groups were elective, trauma, and emergent surgery based on anatomic location and urgency. Univariable comparison used chi-squared tests for relevant variables. Confounders were addressed through multivariable logistic regression with significant variables from univariable analysis. RESULTS: 113 108 total patients met the study criteria. The SSI rate during admission or readmission was 2.9% (n = 3254). Infections during admission and readmission were 1.4% (n = 1560) and 1.5% (n = 1694), respectively. The most common site was organ space (48.6%, n = 1657). Increased infection risk was associated with trauma (OR 1.80 [1.51-2.16] P < .001), emergency surgery (OR 1.31 [1.17-1.47] P < .001), large bowel surgery (OR 2.78 [2.26-3.43] P < .001), and those with three or more comorbidities (OR 2.03 [1.69-2.45] P < .001). Investor-owned hospitals (OR .65 [.56-.76] P < .001) and highest quartile income (OR .80 [.73-.88] P < .001) were associated with decreased infection risk. CONCLUSIONS: Pediatric patients undergoing gastrointestinal surgery face an elevated risk of SSI, especially in trauma and emergency surgeries, particularly with multiple comorbidities. Meanwhile, a reduced risk is observed in high-income and investor-owned hospital settings. Hospitals and surgeons caring for high risk patients should advocate for risk adjustment in value-based payment systems.

Financial Toxicity in Emergency General Surgery: Novel Propensity-Matched Outcome Comparison.

BACKGROUND: Financial toxicity describes the harmful effect of individual treatment costs and fiscal burdens that have a compounding negative impact on outcomes in surgery. While this phenomenon has been widely studied in surgical oncology, the purpose of this study was to perform a novel exploration of the impact of financial toxicity in emergency general surgery (EGS) patients throughout the US. STUDY DESIGN: The Nationwide Readmissions Database for January and February 2018 was queried for all EGS patients aged 18 to 65 years. One-to-one propensity matching was performed with and without risk for financial toxicity. The primary outcome was mortality, and the secondary outcomes were venous thromboembolism (VTE), prolonged length of stay (LOS), and readmission within 30 days. RESULTS: There were 24,154 EGS patients propensity matched. The mortality rate was 0.2% (n = 39), and the rate of VTE was 0.5% (n = 113). With financial toxicity, there was no statistically significant difference for mortality (p = 0.08) or VTE (p = 0.30). The rate of prolonged LOS was 6.2% (n = 824), and the risk was increased with financial toxicity (risk ratio 1.24 [1.12 to 1.37]; p < 0.001). The readmission rate was 7.0% (n = 926), and the risk with financial toxicity was increased (risk ratio 1.21 [1.10 to 1.33]; p < 0.001). The mean count of comorbidities per patient per admission during readmission within 1 year with financial toxicity was 2.1 ± 1.9 versus 1.8 ± 1.7 without (p < 0.001). CONCLUSIONS: Despite little difference in the rate of mortality or VTE, EGS patients at risk for financial toxicity have an increased risk of readmission and longer LOS. Fewer comorbidities were identified at index admission than during readmission in patients at risk for financial toxicity. Future studies aimed at reducing this compounding effect of financial toxicity and identifying missed comorbidities have the potential to improve EGS outcomes.