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CD8+ tissue-resident memory T cells (CD8+ TRM) play an important role in mediating immune responses against HIV in the gastrointestinal (GI) mucosa. Antiretroviral therapy (ART) successfully supresses HIV replication in the blood, but fails to restore GI homeostasis, particularly within gut associated lymphoid tissue (GALT). The importance of cellular metabolism in shaping CD8+ TRM antiviral function has emerged as a crucial aspect of general immunoregulation. To gain better insight into the immunoregulation of CD8+ TRM during HIV, we characterized the function of blood and colon CD8+ T cells in people with HIV (PWH) on ART and HIV-uninfected individuals. We show that a higher proportion of activated CD8+ TRM persisted in the colon of PWH on ART, and these cells exhibited weaker immune response and compromised mitochondrial function compared to their peripheral counterparts. We also observed decreased mitochondrial function in CD8+ T cell in the colon compared to peripheral blood in PWH on ART. The study indicates that mitochondrial bioenergetic properties may be an indicator of colonic CD8+ TRM dysfunction in PWH on ART and highlights the importance of understanding cellular metabolism in shaping CD8+ TRM function to develop targeted immunotherapies for PWH.

Smoking and HIV-1 infection are risk factors for COPD, which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8+ T cells, and CD8+ T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T cell dynamics in patients at risk of COPD. Bronchoalveolar lavage (BAL), endobronchial brushings and blood from HIV-1 infected and uninfected non-smokers and smokers were analyzed by flow cytometry, and lungs were imaged by computed tomography. Chemokines were measured in BAL fluid, and CD8+ T cell chemotaxis in the presence of cigarette smoke extract was assessed in vitro. HIV-1 infection increased CD8+ T cells in the BAL, but this increase was abrogated by smoking. Smokers had reduced BAL levels of the T cell-recruiting chemokines CXCL10 and CCL5, and cigarette smoke extract inhibited CXCL10 and CCL5 production by macrophages and CD8+ T cell transmigration in vitro. In contrast to the BAL, CD8+ T cells in endobronchial brushings were increased in HIV-1 infected smokers, driven by an accumulation of effector memory T cells in the airway mucosa and an increase in tissue resident memory T cells. Mucosal CD8+ T cell numbers inversely correlated with lung aeration, suggesting an association with inflammation and remodeling. HIV-1 infection and smoking lead to retention of CD8+ T cells within the airway mucosa.

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive toMycobacterium tuberculosis(Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current- and never-smokers by performing single-cell RNA-sequencing (scRNA-seq), flow cytometry, and functional assays. We observed enrichment of immature inflammatory monocytes in the lungs of smokers compared to non-smokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease (COPD). Using integrative scRNA-seq and flow cytometry, we identify CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provide evidence that recruitment of monocytes into the lung is mediated by CCL11 binding to CCR2. We also show that these cells exhibit elevated inflammatory responses upon exposure toMtband accelerated intracellular growth ofMtbcompared to mature macrophages. This elevatedMtbgrowth could be inhibited with an anti-inflammatory small molecule, providing a direct connection between smoking-induced pro-inflammatory states and permissiveness toMtbgrowth. Our findings suggest a model in which smoking leads to recruitment of immature inflammatory monocytes from the periphery to the lung via CCL11-CCR2 interactions, which results in the accumulation of theseMtbpermissive cells in the airway. This work defines how smoking may lead to increased susceptibility toMtband identifies novel host-directed therapies to reduce the burden of TB among those who smoke.One Sentence SummaryInflammatory monocytes are recruited to the airways of smokers where they may contribute to more rapid growth ofMycobacterium tuberculosisin the lungs.

Alveolar macrophages (AMs) are critical for defense against airborne pathogens and AM dysfunction is thought to contribute to the increased burden of pulmonary infections observed in individuals living with HIV-1 (HIV). While HIV nucleic acids have been detected in AMs early in infection, circulating HIV during acute and chronic infection is usually CCR5 T cell-tropic (T-tropic) and enters macrophages inefficiently in vitro. The mechanism by which T-tropic viruses infect AMs remains unknown. We collected AMs by bronchoscopy performed in HIV-infected, antiretroviral therapy (ART)-naive and uninfected subjects. We found that viral constructs made with primary HIV envelope sequences isolated from both AMs and plasma were T-tropic and inefficiently infected macrophages. However, these isolates productively infected macrophages when co-cultured with HIV-infected CD4+ T cells. In addition, we provide evidence that T-tropic HIV is transmitted from infected CD4+ T cells to the AM cytosol. We conclude that AM-derived HIV isolates are T-tropic and can enter macrophages through contact with an infected CD4+ T cell, which results in productive infection of AMs. CD4+ T cell-dependent entry of HIV into AMs helps explain the presence of HIV in AMs despite inefficient cell-free infection, and may contribute to AM dysfunction in people living with HIV.

To characterize temporal trends and outcomes of delivery hospitalization with maternal congenital heart disease (CHD). For this repeated cross-sectional analysis, deliveries to women aged 15–54 years with maternal CHD were identified in the 2000–2018 National Inpatient Sample. Temporal trends in maternal CHD were analyzed using joinpoint regression to estimate the average annual percentage change (AAPC) with 95% CIs. The relationship between maternal CHD and several adverse maternal outcomes was analyzed with log-linear regression models. Risk for adverse outcomes in the setting of maternal CHD was further characterized based on additional diagnoses of cardiac comorbidity including congestive heart failure, arrhythmia, valvular disease, pulmonary disorders, and history of thromboembolism. Of 73,109,790 delivery hospitalizations, 51,841 had a diagnosis of maternal CHD (7.1 per 10,000). Maternal CHD rose from 4.2 to 10.9 per 10,000 deliveries (AAPC 4.8%, 95% CI 4.2%, 5.4%). Maternal CHD deliveries with a cardiac comorbidity diagnosis also increased from 0.6 to 2.6 per 10,000 from 2000 to 2018 (AAPC 8.4%, 95% CI 6.3%, 10.6%). Maternal CHD was associated with severe maternal morbidity (adjusted risk ratios [aRR] 4.97, 95% CI 4.75, 5.20), cardiac severe maternal morbidity (aRR 7.65, 95% CI 7.14, 8.19), placental abruption (aRR 1.30, 95% 1.21, 1.38), preterm delivery (aRR 1.47, 95% CI 1.43, 1.51), and transfusion (aRR 2.28, 95% CI 2.14, 2.42). Risk for severe morbidity (AAPC 4.7%, 95% CI 2.5%, 6.9%) and cardiac severe morbidity (AAPC 4.7%, 95% CI 2.5%, 6.9%) increased significantly among women with maternal CHD over the study period. The presence of cardiac comorbidity diagnoses was associated with further increased risk. Maternal CHD is becoming more common among US deliveries. Among deliveries with maternal CHD, risk for severe morbidity is increasing. These findings support that an increasing burden of risk from maternal CHD in the obstetric population.

SUMMARY Lung interstitial CD4+ T cells are critical for protection against pulmonary infections, but the fate of this population during HIV-1 infection is not well described. We studied CD4+ T cells in the setting of HIV-1 infection in human lung tissue, humanized mice, and a Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) nonhuman primate co-infection model. Infection with a CCR5-tropic strain of HIV-1 or SIV results in severe and rapid loss of lung interstitial CD4+ T cells but not blood or lung alveolar CD4+ T cells. This is accompanied by high HIV-1 production in these cells in vitro and in vivo. Importantly, during early SIV infection, loss of lung interstitial CD4+ T cells is associated with increased dissemination of pulmonary Mtb infection. We show that lung interstitial CD4+ T cells serve as an efficient target for HIV-1 and SIV infection that leads to their early depletion and an increased risk of disseminated tuberculosis., Graphical Abstract, In Brief Corleis et al. show that lung parenchymal CD4+ T cells are permissive to HIV-1-dependent cell death. CD4+ T cell loss is highly significant in the interstitium but not the alveolar space, and loss of interstitial CD4+ T cells is associated with extrapulmonary dissemination of M. tuberculosis.