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BACKGROUND: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. METHODS: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. RESULTS: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. CONCLUSION: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.
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Infecciones por VIH , Humanos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Femenino , Persona de Mediana Edad , Adulto , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/metabolismo , Fumar/efectos adversos , Líquido del Lavado Bronquioalveolar/inmunología , Antirretrovirales/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Pulmón/inmunología , Pulmón/efectos de los fármacos , Pulmón/metabolismoRESUMEN
BACKGROUND: Socioeconomic status (SES) is a driver of health disparities and chronic diseases. People with HIV (PWH) are at risk for chronic liver diseases. We evaluated the association between low SES and hepatic outcomes in PWH. METHODS: We included PWH from a prospective cohort. SES was assessed by the Pampalon material and social deprivation index to classify the cohort into quintiles of deprivation. Multivariable linear regression was used to investigate associations of material and social deprivation with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) as markers of hepatic fibrosis and steatosis, respectively. Incidence of outcomes was evaluated through survival analysis. RESULTS: Among the 804 PWH included, 45% and 72% were living in areas of the highest material and social deprivation, respectively. Materially deprived PWH were more frequently female and of non-white ethnicity and had higher prevalence of metabolic comorbidities. After adjustments, material deprivation correlated with increased LSM (ß = 1.86, 95% CI 0.53-3.17) but not with CAP (ß = 6.47, 95% CI -5.55-18.49). Patients were observed for a median follow-up of 3.8 years. Incidence of liver-related events was higher in most materially deprived compared to most privileged PWH (hazard ratio 3.03, 95% CI 1.03-8.92), while there was no difference in extrahepatic outcomes or all-cause mortality. Social deprivation showed no association with either LSM or clinical outcomes. CONCLUSIONS: Living in materially deprived neighbourhoods as a proxy for lower SES, is associated with LSM and liver-related events in PWH. Future strategies should explore mechanisms underlying these relationships and whether enhanced material security improves hepatic outcomes.
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BACKGROUND: Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) (PLWH), as do initial responses to a third dose. METHODS: We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls. RESULTS: Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. CONCLUSION: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.
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COVID-19 , Infecciones por VIH , Humanos , VIH , Vacunas contra la COVID-19 , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos , Vacunación , Infecciones por VIH/tratamiento farmacológico , Anticuerpos AntiviralesRESUMEN
This study examined the feasibility of using ecological momentary assessment (EMA) to disentangle medicinal cannabis use (MCU) from recreational cannabis use (RCU) among people living HIV (PLWH). Over a 14-day period, PLWH (N = 29) who engaged in both MCU and RCU completed a smartphone-based survey before and after every cannabis use event assessing general motivation for cannabis use (MCU-only, RCU-only, or mixed MCU/RCU), cannabis use behavior, and several antecedents and outcomes of cannabis use. A total of 739 pre-cannabis surveys were completed; 590 (80%) of the prompted post-cannabis surveys were completed. Motives for cannabis use were reported as MCU-only on 24%, RCU-only on 30%, and mixed MCU/RCU on 46% of pre-cannabis surveys. Mixed effects models examined within-person differences across MCU-only, RCU-only, and mixed MCU/RCU events. Results showed that relative to RCU-only events, MCU-only events were more likely to involve symptom management and drug substitution motives, physical and sleep-related symptoms, solitary cannabis use, and use of cannabis oils and sprays; MCU-only events were less likely to involve relaxation, happiness, and wellness motives, cannabis flower use, and positive cannabis consequences. Differences between mixed MCU/RCU and RCU-only events were similar, except that mixed MCU/RCU events were additionally associated with stress reduction motives and symptoms of anxiety and depression. Findings support the feasibility of partially disentangling MCU and RCU behavior among PLWH who engage in concurrent MCU and RCU. This study highlights the need for more EMA studies isolating MCU from RCU to inform ongoing changes to cannabis policies.
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Cannabis , Infecciones por VIH , Marihuana Medicinal , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , VIH , Evaluación Ecológica Momentánea , Ansiedad/epidemiologíaRESUMEN
Understanding the roots of Covid-19 vaccine hesitancy in at-risk groups, such as persons living with HIV (PLWH), is of utmost importance. We developed a modified Vaccine Hesitancy Scale (VHS) questionnaire using items from the National Advisory Committee on Immunization Acceptability Matrix. To examine factors associated with receiving COVID-19 vaccine and the link between vaccine attitudes and beliefs with vaccine behavior, PLWH were recruited via social media and community-based organizations (February-May 2022). Descriptive statistics were used to summarize results. Total VHS score was generated by adding Likert scale scores and linear regression models used to compare results between participants who received or did not receive COVID-19 vaccines. Logistic regression models were used to identify factors associated with vaccine uptake. A total of 246 PLWH indicated whether they received a COVID-19 vaccine. 89% received ≥ 1 dose. Mean total VHS(SD) for persons having received ≥ 1 COVID-19 vaccine was 17.8(6.2) vs. 35.4(9.4) for participants not having received any COVID-19 vaccine. Persons who received ≥ 1 dose were significantly older than those who had not received any (48.4 ± 13.8 vs. 34.0 ± 7.7 years, p < 0.0001). The majority of participants considered COVID-19 vaccination important for their health(81.3%) and the health of others(84.4%). Multivariate logistic regression revealed the odds of taking ≥ 1dose were increased 2.4-fold [95% CI 1.6, 3.5] with each increase in age of 10 years (p < 0.0001). Sex and ethnicity were not different between groups. In conclusion, PLWH accept COVID-19 vaccines for both altruistic and individual reasons. With evolving recommendations and increasing numbers of booster vaccines, we must re-examine the needs of PLWH regularly.
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COVID-19 , Infecciones por VIH , Humanos , Niño , Vacunas contra la COVID-19 , COVID-19/epidemiología , COVID-19/prevención & control , Canadá/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Etnicidad , VacunaciónRESUMEN
People living with HIV have high burdens of chronic lung disease, lung cancers, and pulmonary infections despite antiretroviral therapy (ART). The rates of tobacco smoking by people living with HIV vastly exceed that of the general population. Furthermore, we showed that HIV can persist within the lung mucosa despite long-term ART. As CD8 T cell cytotoxicity is pivotal for controlling viral infections and eliminating defective cells, we explored the phenotypic and functional features of pulmonary versus peripheral blood CD8 T cells in ART-treated HIV+ and uninfected controls. Bronchoalveolar lavage fluid and matched blood were obtained from asymptomatic ART-treated HIV+ smokers (n = 11) and nonsmokers (n = 15) and uninfected smokers (n = 7) and nonsmokers (n = 10). CD8 T cell subsets and phenotypes were assessed by flow cytometry. Perforin/granzyme B content, degranulation (CD107a expression), and cytotoxicity against autologous Gag peptide-pulsed CD4 T cells (Annexin V+) following in vitro stimulation were assessed. In all groups, pulmonary CD8 T cells were enriched in effector memory subsets compared with blood and displayed higher levels of activation (HLA-DR+) and exhaustion (PD1+) markers. Significant reductions in proportions of senescent pulmonary CD28-CD57+ CD8 T cells were observed only in HIV+ smokers. Pulmonary CD8 T cells showed lower perforin expression ex vivo compared with blood CD8 T cells, with reduced granzyme B expression only in HIV+ nonsmokers. Bronchoalveolar lavage CD8 T cells showed significantly less in vitro degranulation and CD4 killing capacity than blood CD8 T cells. Therefore, pulmonary mucosal CD8 T cells are more differentiated, activated, and exhausted, with reduced killing capacity in vitro than blood CD8 T cells, potentially contributing to a suboptimal anti-HIV immune response within the lungs.
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Antirretrovirales/uso terapéutico , Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH-1/fisiología , Mucosa Respiratoria/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto , Degranulación de la Célula , Células Cultivadas , Senescencia Celular , Citotoxicidad Inmunológica , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Evasión Inmune , Memoria Inmunológica , Inmunofenotipificación , Activación de Linfocitos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Few studies have examined preventative behaviour practices with respect to COVID-19 among people living with HIV (human immunodeficiency virus). Using a cross-sectional survey from a Canadian Institutes of Health Research Canadian HIV Trials Network study (CTN 328) of people living with HIV on vaccine immunogenicity, we examined the relationships between participant characteristics and behavioural practices intended to prevent COVID-19 infection. Participants living in four Canadian urban centers were enrolled between April 2021-January 2022, at which time they responded to a questionnaire on preventative behaviour practices. Questionnaire and clinical data were combined to explore relationships between preventive behaviours and (1) known COVID-19 infection pre-enrolment, (2) multimorbidity, (3) developing symptomatic COVID-19 infection, and (4) developing symptomatic COVID-19 infection during the Omicron wave. Among 375 participants, 49 had COVID-19 infection pre-enrolment and 88 post-enrolment. The proportion of participants reporting always engaging in preventative behaviours included 87% masking, 79% physical distancing, 70% limiting social gatherings, 65% limiting contact with at-risk individuals, 33% self-isolating due to symptoms, and 26% self-quarantining after possible exposure. Participants with known COVID-19 infection pre-enrolment were more likely to self-quarantine after possible exposure although asymptomatic (65.0% vs 23.4%, p < 0.001; Chi-square test). Participants with multiple comorbidities more likely endorsed physical distancing (85.7% vs 75.5%, p = 0.044; Chi-square test), although this was not significant in logistic regression analysis adjusted for age, sex, race, number of household members, number of bedrooms/bathrooms in the household per person, influenza immunization, and working in close physical proximity to others. Overall, participants reported frequent practice of preventative behaviours.
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COVID-19 , Infecciones por VIH , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , VIH , Estudios Transversales , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Canadá/epidemiologíaRESUMEN
BACKGROUND: Many people living with HIV (PLWH) use cannabis for medicinal reasons. Patients' knowledge of the tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations of the cannabis products they use may be important in helping patients achieve symptom relief while guarding against potential risks of cannabis use. However, no studies have examined cannabinoid concentration knowledge among PLWH. METHOD: PLWH (N = 29; 76% men, mean age 47 years) reporting cannabis use for both medicinal and nonmedicinal reasons completed daily surveys over 14 days assessing cannabis products used, knowledge of cannabinoid concentrations of cannabis products used, cannabis use motives (medicinal, nonmedicinal, both), and positive and negative cannabis-related consequences. Across the 361 cannabis use days captured on the daily surveys, at least some knowledge of cannabinoid concentrations was reported on an average of 43.1% (for THC) and 26.6% (for CBD) of the days. RESULTS: Generalized linear mixed models revealed that participants were more likely to report knowing THC and CBD concentrations on days when they used non-flower forms of cannabis relative to days when they used cannabis flower only. Participants who used cannabis for medicinal reasons on a greater proportion of days had greater knowledge of cannabinoid concentration overall across days. Further, greater overall knowledge of cannabinoid concentrations was associated with fewer reported negative cannabis-related consequences. CONCLUSIONS: Findings suggest that among PLWH, knowledge of cannabinoid concentrations may be higher when using non-flower cannabis products and among those reporting primarily medicinal cannabis use. Moreover, knowledge of cannabinoid concentration may protect against negative cannabis-related consequences in this population.
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The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro-infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure.IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4+ T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus-initially developed as a cancer therapy-is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field.
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Antirretrovirales/uso terapéutico , Infecciones por VIH/terapia , Interferón-alfa/uso terapéutico , Macrófagos/virología , Virus Oncolíticos/fisiología , Rhabdoviridae/fisiología , Animales , Chlorocebus aethiops , Células HEK293 , VIH-1 , Humanos , Células VeroRESUMEN
People living with HIV (PLWH) often have worse health outcomes compared to HIV-uninfected individuals. We characterized PLWH followed at a tertiary care clinic in Montreal who acquired COVID-19 and described their outcomes during the first wave of the pandemic. A retrospective chart review was performed for PLWH followed at the Chronic Viral Illness Service with a positive COVID-19 nasopharyngeal PCR or symptoms suggestive of COVID-19 between 1 March and 15 June 2020. Data on demographics, socioeconomic status, co-morbidities and severity of COVID-19 and outcomes were extracted. Of 1702 individuals, 32 (1.9%) had a positive COVID-19 test (n = 24) or symptoms suspicious for COVID-19 (n = 3). Median age was 52 years [IQR 40, 62]. Nearly all (97%) earned $34,999 Canadian dollars or less. Eleven (34%) individuals worked in long-term care (LTC) homes while 5 (6%) lived in LTC homes. Median CD4 count was 566 cells/mm3 [347, 726] and six had detectable plasma HIV viral loads. Median duration of HIV was 17 years [7, 22] and 30 individuals had been prescribed antiretroviral therapy. Five persons were asymptomatic. Of symptomatic persons, 21 (12%), 1 (4%) and 3 (12%) individuals had mild, moderate and severe disease, respectively. Three individuals died with COVID-19. In one case, the cause of death was due to COVID-19, whereas in the other two cases, the individuals died with positive COVID-19 test results but the immediate cause of death is unclear. PLWH who tested positive for COVID-19 had low socioeconomic status and had employment or living conditions that put them at high risk. PLWH may be disproportionately impacted by the social determinants of health which predispose them to COVID-19.
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COVID-19 , Infecciones por VIH , COVID-19/epidemiología , Canadá , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Persona de Mediana Edad , Pandemias , Estudios Retrospectivos , SARS-CoV-2 , Centros de Atención TerciariaRESUMEN
Nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease (ALD), and viral hepatitis are the main causes of morbidity and mortality related to chronic liver diseases (CLDs) worldwide. New therapeutic approaches to prevent or reverse these liver disorders are thus emerging. Although their etiologies differ, these CLDs all have in common a significant dysregulation of liver metabolism that is closely linked to the perturbation of the hepatic endocannabinoid system (eCBS) and inflammatory pathways. Therefore, targeting the hepatic eCBS might have promising therapeutic potential to overcome CLDs. Experimental models of CLDs and observational studies in humans suggest that cannabis and its derivatives may exert hepatoprotective effects against CLDs through diverse pathways. However, these promising therapeutic benefits are not yet fully validated, as the few completed clinical trials on phytocannabinoids, which are thought to hold the most promising therapeutic potential (cannabidiol or tetrahydrocannabivarin), remained inconclusive. Therefore, expanding research on less studied phytocannabinoids and their derivatives, with a focus on their mode of action on liver metabolism, might provide promising advances in the development of new and original therapeutics for the management of CLDs, such as NAFLD, ALD, or even hepatitis C-induced liver disorders.
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Cannabidiol , Cannabinoides , Cannabis , Hepatopatías Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Cannabis/metabolismo , Endocannabinoides/metabolismo , Humanos , Hepatopatías Alcohólicas/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológicoRESUMEN
The lungs are relatively unexplored anatomical human immunodeficiency virus (HIV) reservoirs in the antiretroviral therapy (ART) era. Double negative (DN) T cells are a subset of T cells that lack expression of CD4 and CD8 (CD4- CD8-) and may have both regulatory and effector functions during HIV infection. Notably, circulating DN T cells were previously described as cellular HIV reservoirs. Here, we undertook a thorough analysis of pulmonary versus blood DN T cells of people living with HIV (PLWH) under ART. Bronchoalveolar lavage (BAL) fluid and matched peripheral blood were collected from 35 PLWH on ART and 16 uninfected volunteers without respiratory symptoms. Both PLWH and HIV-negative (HIV-) adults displayed higher frequencies of DN T cells in BAL versus blood, and these cells mostly exhibited an effector memory phenotype. In PLWH, pulmonary mucosal DN T cells expressed higher levels of HLA-DR and several cellular markers associated with HIV persistence (CCR6, CXCR3, and PD-1) than blood. We also observed that DN T cells were less senescent (CD28- CD57+) and expressed less immunosuppressive ectonucleotidase (CD73/CD39), granzyme B, and perforin in the BAL fluid than in the blood of PLWH. Importantly, fluorescence-activated cell sorter (FACS)-sorted DN T cells from the BAL fluid of PLWH under suppressive ART harbored HIV DNA. Using the humanized bone marrow-liver-thymus (hu-BLT) mouse model of HIV infection, we observed higher infection frequencies of lung DN T cells than those of the blood and spleen in both early and late HIV infection. Overall, our findings show that HIV is seeded in pulmonary mucosal DN T cells early following infection and persists in these potential cellular HIV reservoirs even during long-term ART.IMPORTANCE Reservoirs of HIV during ART are the primary reasons why HIV/AIDS remains an incurable disease. Indeed, HIV remains latent and unreachable by antiretrovirals in cellular and anatomical sanctuaries, preventing its eradication. The lungs have received very little attention compared to other anatomical reservoirs despite being immunological effector sites exhibiting characteristics ideal for HIV persistence. Furthermore, PLWH suffer from a high burden of pulmonary non-opportunistic infections, suggesting impaired pulmonary immunity despite ART. Meanwhile, various immune cell populations have been proposed to be cellular reservoirs in blood, including CD4- CD8- DN T cells, a subset that may originate from CD4 downregulation by HIV proteins. The present study aims to describe DN T cells in human and humanized mice lungs in relation to intrapulmonary HIV burden. The characterization of DN T cells as cellular HIV reservoirs and the lungs as an anatomical HIV reservoir will contribute to the development of targeted HIV eradication strategies.
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Infecciones por VIH/inmunología , Infecciones por VIH/virología , Pulmón/inmunología , Pulmón/virología , Linfocitos T/inmunología , Linfocitos T/virología , Animales , Líquido del Lavado Bronquioalveolar/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Receptor de Muerte Celular Programada 1 , Receptores CCR6/sangre , Receptores CXCR3/sangreRESUMEN
BACKGROUND: Regenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH. METHODS: Plasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)-uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers. RESULTS: Cross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH. CONCLUSIONS: Plasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.
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Proteínas de Unión a Ácidos Grasos/sangre , Infecciones por VIH/sangre , VIH-1 , Mucosa Intestinal/patología , Proteínas Asociadas a Pancreatitis/sangre , Adulto , Fármacos Anti-VIH/uso terapéutico , Traslocación Bacteriana , Biomarcadores/sangre , Relación CD4-CD8 , Estudios Transversales , Progresión de la Enfermedad , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Interleucinas/sangre , Receptores de Lipopolisacáridos/sangre , Lipopolisacáridos/sangre , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangre , Carga Viral , beta-Glucanos/sangre , Interleucina-22RESUMEN
Lung cancer is the most frequent type of cancer-related death in people living with HIV (PLWH). We conducted a review of primary lung cancers in PLWH at the McGill University Health Centre from 1988-May 2018 to understand potential factors contributing to their development prior to the implementation of a lung cancer screening program. Twenty-seven individuals had a diagnosis of a lung tumor. Of these individuals, 21 (78%) had a primary lung cancer, over 21,428 person-years follow-up. Median age was 54.5 years [25th and 75th percentiles 49.0, 62.0]. Median CD4 count was 185.0 cells/µL [25th and 75th percentiles 54.0, 446.0] and 52% were on antitretroviral therapy with suppressed viral loads. Type of primary lung cancer included: non-small cell lung cancer (n = 15), small-cell lung cancer (n = 4) and bronchial carcinomas (n = 2). Metastatic disease at diagnosis was present in 11 (52%) persons. Survival was a median of 7.5 months from the time of diagnosis [25th and 75th percentiles 2.0, 9.0]. In conclusion, we observed a high proportion of lung cancers detected at very late stages of disease and with metastatic involvement. The implementation of a lung cancer screening program in 2018 should set a stage shift for earlier diagnosis and treatment.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Infecciones por VIH/complicaciones , Neoplasias Pulmonares/diagnóstico , Recuento de Linfocito CD4 , Canadá/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Comorbilidad , Detección Precoz del Cáncer , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Neoplasias Pulmonares/epidemiología , Persona de Mediana EdadRESUMEN
BACKGROUND: Angiocentric lymph proliferative disorder (ALPD) is a granulomatous lymphoproliferative condition associated with various primary and secondary immunodeficiency states. ALPD is so rare that its prevalence has not been established. Typically affecting middle-aged adults, this condition is often found in the context of Epstein Bar Virus infection and consists of angiocentric and angioinvasive pulmonary infiltrates. Herein, we present a biopsy-proven case of a patient manifesting with a viral meningoencephalomyelitis-like picture with brain, spinal cord, renal and splenic lesions. The diagnosis was confirmed to be ALPD in the context of newly diagnosed HIV infection. CASE PRESENTATION: A 35 year-old homosexual man presented with a 5-week history of headaches followed by a 3-week history of horizontal diplopia, limb weakness and right 6th cranial nerve palsy. Lumbar puncture revealed a lymphocytic pleocytosis, high protein and low glucose. Magnetic Resonance Imaging showed scattered lesions throughout the brain and spinal cord and Computed Tomography of the abdomen and pelvis revealed hypodensities involving the kidneys and spleen. HIV testing was positive, with a viral load of 11,096 copies/mL and CD4 count of 324 cells/µL. Serum Epstein Bar virus PCR was positive with 12,434 copies/ml. Right frontal brain biopsy revealed gray matter containing angiogentric cerebritis with organizing infarction but Epstein Bar Virus-in situ preparations were negative and no viral inclusions were identified. A diagnosis of ALPD (also known as lymphomatoid granulomatosis) was made. The patient was initiated on antiretroviral therapy and treated with intravenous rituximab every 3 weeks for 4 cycles and made progressive improvements. By the time of discharge his strength had improved and he was ambulating again although with a walker. Within 2 months, his HIV viral load was suppressed. Magnetic Resonance Imaging of the brain 6 months later revealed interval improvement. At his most recent follow-up, 34 months later, his neurological symptoms had almost completed resolved. CONCLUSION: Albeit rare, ALPD should be considered in the differential diagnosis of central nervous system lesions in persons with HIV once common etiologies have been eliminated. Furthermore, ALPD involving the central nervous system may occur in in the absence of documented EBV infection in the central nervous system.
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Encéfalo/patología , Infecciones por VIH/tratamiento farmacológico , Granulomatosis Linfomatoide/etiología , Médula Espinal/patología , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Encéfalo/diagnóstico por imagen , Homosexualidad Masculina , Humanos , Linfocitos/patología , Granulomatosis Linfomatoide/diagnóstico por imagen , Granulomatosis Linfomatoide/tratamiento farmacológico , Imagen por Resonancia Magnética , Masculino , Rituximab/uso terapéutico , Médula Espinal/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Tryptophan (Trp) catabolism into kynurenine (Kyn) contributes to immune dysfunction in chronic human immunodeficiency virus (HIV) infection. To better define the relationship between Trp catabolism, inflammation, gut mucosal dysfunction, and the role of early antiretroviral therapy (ART), we prospectively assessed patients early after they acquired HIV. METHODS: Forty patients in the early phase of infection were longitudinally followed for 12 months after receiving a diagnosis of HIV infection; 24 were untreated, and 16 were receiving ART. Kyn/Trp ratio, regulatory T-cells (Tregs) frequency, T-cell activation, dendritic cell counts, and plasma levels of gut mucosal dysfunction markers intestinal-type fatty acid-binding protein, soluble suppression of tumorigenicity 2, and lipopolysaccharide were assessed. RESULTS: Compared with healthy subjects, patients in the early phase of infection presented with elevated Kyn/Trp ratios, which further increased in untreated patients but normalized in ART recipients. Accordingly, in untreated subjects, the elevated Treg frequency observed at baseline continued to increase over time. The highest CD8(+) T-cell activation was observed during the early phase of infection and decreased in untreated patients, whereas activation normalized in ART recipients. The Kyn/Trp ratio was positively associated with CD8(+) T-cell activation and levels of inflammatory cytokines (interleukin 6, interferon γ-inducible protein 10, interleukin 18, and tumor necrosis factor α) and negatively associated with dendritic cell frequencies at baseline and in untreated patients. However, ART did not normalize plasma levels of gut mucosal dysfunction markers. CONCLUSIONS: Early initiation of ART normalized enhanced Trp catabolism and immune activation but did not improve plasma levels of gut mucosal dysfunction markers.
Asunto(s)
Infecciones por VIH/inmunología , Mucosa Intestinal/inmunología , Triptófano/inmunología , Adulto , Anciano , Antirretrovirales/uso terapéutico , Biomarcadores/análisis , Células Dendríticas/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Quinurenina/inmunología , Quinurenina/metabolismo , Estudios Longitudinales , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Triptófano/metabolismoRESUMEN
Failure of antiretroviral therapy to eradicate HIV, even in individuals who suppress the virus to undetectable levels, is a consequence of persistent infection in latently infected cells and within anatomical reservoirs. Support for the notion that the lungs are distinct anatomical reservoirs of HIV comes from a spectrum of studies that have documented different levels of HIV within the lungs compared with the peripheral blood. Different HIV variants have also been found within these two compartments, including variants with distinct antiretroviral resistance mutations. Given that macrophages are long-lived cellular reservoirs of HIV because of their resistance to apoptosis, HIV can persist for prolonged periods within alveolar macrophages that are abundant within the lungs. Furthermore, the large number of cells in close proximity within the lungs provides fertile grounds for cell-to-cell spread of HIV. Distinct immunological pressures in the lungs compared with the peripheral blood likely account for differences in HIV levels within these two compartments in addition to the finding of different variants within these regions. Furthermore, coinfections and tobacco may serve as local stimuli to induce further HIV replication within the lungs. Herein, we review the evidence supporting the notion that lungs are important reservoirs of HIV infection, and we discuss various factors influencing HIV burden within these reservoirs.
Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Pulmón/virología , Reservorios de Enfermedades , Humanos , Macrófagos Alveolares/virología , Latencia del VirusRESUMEN
A major research priority for HIV eradication is the elucidation of the events involved in HIV reservoir establishment and persistence. Cell-to-cell transmission of HIV represents an important area of study as it allows for the infection of cell types which are not easily infected by HIV, leading to the establishment of long-lived viral reservoirs. This phenomenon enables HIV to escape elimination by the immune system. This process may also enable HIV to escape suppressive effects of anti-retroviral drugs. During cell-to-cell transmission of HIV, a dynamic series of events ensues at the virological synapse that promotes viral dissemination. Cell-to-cell transmission involves various types of cells of the immune system and this mode of transmission has been shown to have an important role in sexual and mother-to-child transmission of HIV and spread of HIV within the central nervous system and gut-associated lymphoid tissues. There is also evidence that cell-to-cell transmission of HIV occurs between thymocytes and renal tubular cells. Herein, following a brief review of the processes involved at the virological synapse, evidence supporting the role for cell-to-cell transmission of HIV in the maintenance of the HIV reservoir will be highlighted. Therapeutic considerations and future directions for this area of research will also be discussed.
Asunto(s)
Infecciones por VIH/virología , Linfocitos T CD4-Positivos/virología , Sistema Nervioso Central/virología , Células Dendríticas/virología , Reservorios de Enfermedades/virología , Femenino , Tracto Gastrointestinal/virología , VIH/inmunología , VIH/patogenicidad , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Humanos , Sinapsis Inmunológicas/virología , Transmisión Vertical de Enfermedad Infecciosa , Túbulos Renales/virología , Macrófagos/virología , Masculino , EmbarazoRESUMEN
Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia.
Asunto(s)
Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/inmunología , Viremia/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/farmacología , Adenina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Enfermedades Asintomáticas , Relación CD4-CD8 , Linfocitos T CD4-Positivos/virología , ADN Viral/sangre , ADN Viral/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Quimioterapia Combinada , Emtricitabina , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Inmunidad Innata , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico , Raltegravir Potásico , Tenofovir , Viremia/inmunología , Replicación ViralRESUMEN
The numbers of organ donors in Canada and the USA fall short of increasing demand, resulting in increased morbidity, poor health outcomes, higher medical costs and death of many individuals waitlisted for transplantation. In the US, since 2013 when the US HIV Organ Policy Equity (HOPE) Act lifted the ban on organ donation between people living with HIV, the option of using organs from People with HIV became a reality. In Canada, HIV diagnosis was an exclusion criterion to organ donation until 2017, when permission was granted if requirements for 'exceptional distribution' could be met. Still, donation of organs from people with HIV poses challenges. Herein, we overview policies involving donors with HIV in Canada in order to inform healthcare providers, researchers and the community. We also advocate for the need to reassess these policies, highlight educational needs and engage interest in advancing research to inform policy reforms.