RESUMO
Because antiretroviral therapy (ART) is allowing people living with human immunodeficiency virus (PLWH) to survive longer, they are developing more age-related comorbidities. We evaluated the effects of age and gender on the burden of age-related comorbidities among PLWH. In this retrospective real-world study, de-identified data were extracted from the medical charts of 2000 HIV-positive adults on ART across 10 sites in Canada. The prevalence of age-related comorbidities was determined in 6 age subgroups (<30, 30-39, 40-49, 50-59, 60-69, and ≥70 years). The effects of gender on these comorbidities were also examined. Risks of cardiovascular disease and chronic kidney disease (CKD) were calculated using the Framingham and D:A:D equations. Most persons were White (68%), male (87%), and virologically suppressed (94%). The mean age was 50.3 years (57% aged ≥50 years), and mean CD4+ T-cell count was 616 cells/mm3. The most common comorbidities were neuropsychiatric symptoms (61%), overweight/obesity (43%), liver disease (37%), and dyslipidemia (37%). The mean number of comorbidities increased across age subgroups (P < .001). Across all age subgroups, the prevalence of hypertension (P = .04), dyslipidemia (P = .04), CKD (P = .03), bone fragility (P = .03), and depression (P = .02) differed between males and females. Both age (P < .001) and gender (P < .001) impacted cardiovascular disease and CKD risk. Age and gender influenced the burden, types, and risks of age-related comorbidities in PLWH in this Canadian cohort. These comorbidities should be diagnosed and treated in routine clinical practice.
Assuntos
Doenças Cardiovasculares , Infecções por HIV , Insuficiência Renal Crônica , Adulto , Canadá/epidemiologia , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Insuficiência Renal Crônica/epidemiologia , Estudos RetrospectivosRESUMO
There is limited understanding on healthcare utilization and costs of age-related comorbidities such as cardiovascular, bone and renal disease/disorder in people living with human immunodeficiency virus, so we compared comorbidity prevalence and associated healthcare utilization and costs. Through the Quebec health insurance database, people living with human immunodeficiency virus on antiretroviral therapy for ≥6 months from January 2006 to June 2012 were categorized by their comorbidity status using International Classification of Diseases (ICD)-9 codes, and controls without human immunodeficiency virus diagnosis or antiretroviral therapy use were age and gender matched. We compared healthcare utilization and costs. A total of 3,905 people living with human immunodeficiency virus and 11,715 control individuals were included. The mean age of people living with human immunodeficiency virus was 45.3 years and 77.3% were men. Prevalence of comorbidities was higher and occurred earlier in people living with human immunodeficiency virus and increased with older age regardless of human immunodeficiency virus status. Interestingly, bone comorbidity was high (37%) and 5-fold greater in people living with human immunodeficiency virus <20 years than the controls. Polypharmacy and comorbidity scores were greater in people living with human immunodeficiency virus than controls (p<0.01), as were cardiovascular, bone and renal comorbidities (40.3%, 26.0% and 5.5%, respectively; p<0.01). People living with human immunodeficiency virus had higher healthcare utilization and costs than controls largely due to longer hospital stays and prescriptions. Mean total healthcare cost/person/year for people living with human immunodeficiency virus was CAD$6,248 and was highest for those with renal disease (CAD$19,617). Comorbidities in people living with human immunodeficiency virus are more prevalent, occur earlier and incur a higher burden on the healthcare system; earlier screening and improved preventative and management strategies may reduce the burden to people living with human immunodeficiency virus and to the healthcare system.
Assuntos
Infecções por HIV , Comorbidade , Atenção à Saúde , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Quebeque/epidemiologia , Estudos RetrospectivosRESUMO
OBJECTIVE: To assess whether probiotic supplementation may reduce disease-linked systemic immune activation in people living with HIV with the immunologic nonresponder phenotype. DESIGN: Phase 2b, randomized, double-blind, placebo-controlled pilot trial. METHODS: HIV-positive individuals with blood CD4+ T-cell counts <350/mm3 despite viral suppression were randomized to 2:1 to receive De Simone Formulation Probiotic (DSFP; "Visbiome" commercially) or placebo for 48 weeks; target enrollment was 36 patients. The primary endpoint was the change in blood CD8+ T-cell coexpression of human leukocyte antigen-DR isotype and CD38 ("CD8 activation"). Secondary endpoints included biomarkers of inflammation, immune reconstitution, bacterial translocation, and gut permeability. Adjusted linear regression and linear mixed regression methods evaluated the differences between study arms from baseline to week 48. Study monitoring was performed by the CIHR Canadian HIV Trials Network Data Safety Monitoring Committee. RESULTS: Nineteen patients received DSFP, whereas 10 received placebo. One probiotic arm patient withdrew early. Blood CD8 activation increased 0.82 percentage points (pp) in the probiotic arm (95% confidence interval: -1.23 to 2.87;) and decreased by 2.06 pp in the placebo arm (-4.81 to 0.70; between arms P = 0.097). CD4+ T-cell activation (%HLA-DR+) decreased in the placebo arm [-3.79 pp (-7.32 to -0.26)] but increased in the probiotic arm [1.64 (-0.98 to 4.26); between arms P = 0.018]. No differences were observed in plasma or urine biomarkers of inflammation or microbial translocation. CONCLUSIONS: Blood immune activation markers in immunologic nonresponder individuals on effective antiretroviral treatment were not reduced by supplementation with DSFP; CD4+ T-cell activation may have been increased.
Assuntos
Infecções por HIV , Probióticos , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Canadá , Antígenos HLA-DR , Humanos , Probióticos/uso terapêuticoRESUMO
OBJECTIVE: Standard antiretroviral therapy (ART) is slow to reverse gut mucosal immune defects that cause persistent inflammation and immune activation. We examined whether intensifying early-administered ART through the addition of maraviroc and raltegravir would accelerate their resolution. DESIGN: ART-naïve men with early HIV infection were randomized in a double-blind manner to receive ART (emtricitabine/tenofovir disoproxil fumarateâ+âlopinavir/ritonavir), together with either combined placebo or raltegravirâ+âmaraviroc, for 48 weeks. In a predefined substudy, paired blood and sigmoid biopsies were collected at baseline and week 48. Mucosal CD4 T-cell immune subsets (Th1, Th17, and Th22 cells), CD8 T-cell immune activation, and soluble blood markers of inflammation (IL-6, IL-17, macrophage inflammatory protein-1b, soluble CD14, and IL-10) and coagulation (D-dimer) were measured. RESULTS: A total of 22 participants were enrolled, a median of 4 months after HIV acquisition. At baseline, there was substantial systemic and mucosal immune activation, and gut CD4 T-cell numbers, Th22 cell numbers, and Th17 cell function were reduced compared with controls. Early ART restored gut Th22 numbers, improved but did not restore overall CD4 numbers, and had no impact on Th17 function. Plasma levels of soluble CD14 and D-dimer normalized, whereas other inflammatory cytokines were reduced but not normalized. ART intensification had no impact on any blood or gut immune parameters. CONCLUSION: Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Imunidade nas Mucosas/efeitos dos fármacos , Inflamação/sangue , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Adulto , Biomarcadores/sangue , Canadá , Cicloexanos/farmacologia , Método Duplo-Cego , Quimioterapia Combinada , Produtos de Degradação da Fibrina e do Fibrinogênio/efeitos dos fármacos , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/imunologia , Humanos , Inflamação/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Maraviroc , Pessoa de Meia-Idade , Estudos Prospectivos , Raltegravir Potássico/farmacologia , Células Th17/efeitos dos fármacos , Resultado do Tratamento , Triazóis/farmacologia , Adulto JovemRESUMO
OBJECTIVES: Despite substantial improvements in HIV outcomes with combination antiretroviral therapy (cART), morbidity and mortality remain above population norms. The gut mucosal immune system is not completely restored by cART, and the resultant microbial translocation may contribute to chronic inflammation, inadequate CD4 T-cell recovery, and increased rates of serious non-AIDS events. Since the microbial environment surrounding a CD4 T cell may influence its development and function, we hypothesize that probiotics provided during cART might reduce inflammation and improve gut immune health in HIV-positive treatment-naïve individuals (PROOV IT I) and individuals with suboptimal CD4 recovery on cART (PROOV IT II). METHODS: These prospective, double-blinded, randomized, placebo-controlled, multicenter pilot studies will assess the impact of the probiotic Visbiome at 900 billion bacteria daily. Forty HIV positive cART-naïve men will be randomized in the PROOV IT I study, coincident with antiretroviral initiation, and be followed for 24 weeks. In PROOV IT II, 36 men on cART, but with a CD4 T-cell count below 350 cells/mm(3) will be followed for 48 weeks. The primary outcome for both studies is the comparison of blood CD8 T-cell immune activation. Secondary analyses will include comparison of blood inflammatory biomarkers, microbial translocation, blood and gut immunology and HIV levels, the bacterial community composition, diet, intestinal permeability, and the safety, adherence and tolerability of the study product. DISCUSSION: These studies will evaluate the ability of probiotics as a safe and tolerable therapeutic intervention to reduce systemic immune activation and to accelerate gut immune restoration in people living with HIV.
Assuntos
Protocolos Clínicos , Gastroenterite/imunologia , Gastroenterite/terapia , Infecções por HIV/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Probióticos/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Biomarcadores , Contagem de Linfócito CD4 , Gastroenterite/patologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunomodulação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Ativação Linfocitária/imunologia , Permeabilidade , Projetos de PesquisaRESUMO
Background. Persistent human immunodeficiency virus (HIV) within the CD4(+) T-cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication. Methods. A prospective, randomized, double-blinded, placebo-controlled pilot trial enrolled 32 participants with documented early (<6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4(+) T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection. Results. Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was -1.03 log DNA copies/10(6) CD4(+) T cells versus -.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4(+) T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent. Conclusions. Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir.
RESUMO
BACKGROUND: The hallmark of HIV infection is progressive but variable rates of systemic and mucosal CD4 depletion, leading to immunodeficiency. The impact of early HIV infection on cervical CD4 T-cell populations in humans remains poorly described. METHODS: We analyzed cytobrush-derived immune cells by flow cytometry and cytokines in cervicovaginal lavage from participants in early HIV (<6 months postinfection), chronic HIV, and HIV-uninfected controls. RESULTS: CD4:CD8 ratios declined rapidly in both the cervix and the blood following HIV infection. In contrast, absolute cervical CD4 T-cell counts in early HIV were comparable to HIV-uninfected participants, declining only in chronic infection. Early HIV infection was associated with increases in RANTES and MIP3a in cervicovaginal fluids. Concurrently, slight increases in activated cells (CD38HLA-DR) and higher levels of CTLA4 expression on Tregs in the cervix were observed. Although study groups did not differ with respect to levels of CCR5, integrin B7, or CD69, the frequencies of Th17 cells (defined as CCR6CCR10) was reduced by >10-fold in early HIV infection and Th1 cells (defined as CCR6CXCR3) were reduced by >2-fold. Although CCR6CCR10 cells did not differ in HIV receptor expression, these cells produced higher levels of interferon gamma and interleukin 17. CONCLUSIONS: These data support the model of initial CD4 T-cell depletion followed by overall T-cell influx in response to infection and concomitant increases in immune activation, inflammation, and regulatory markers. These data are among the earliest characterization of the cellular milieu in the female genital tract following male-to-female HIV transmission.
Assuntos
Colo do Útero/imunologia , Infecções por HIV/imunologia , Células Th17/citologia , Adulto , Relação CD4-CD8 , Linhagem Celular , Estudos de Coortes , Feminino , HIV-1 , Humanos , Imunofenotipagem , Receptores de Quimiocinas/metabolismoRESUMO
Elite controllers (ECs) maintain undetectable HIV viral loads without antiretroviral therapy (ART) but are at increased risk of serious non-AIDS conditions (SNA). We assessed the impact of ART in ECs on gut immune dysfunction and biomarkers predicting SNA (blood CD4/CD8 ratio, plasma IL-6, D-dimer levels). At baseline, ECs had elevated IL-6 and D-dimer levels and reduced CD4/CD8 ratio compared with HIV-uninfected controls, but no difference in microbial translocation or gut CD4 subsets. ART increased CD4/CD8 ratio but did not normalize IL-6 and D-dimer levels. EC SNA pathogenesis may be independent of gut immune dysfunction, and resolution may require prolonged ART.
Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Translocação Bacteriana , Trato Gastrointestinal/imunologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Adulto , Idoso , Biomarcadores , Relação CD4-CD8 , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
A rare subset of IL-10-producing B cells, named regulatory B cells (Bregs), suppresses adaptive immune responses and inflammation in mice. In this study, we examined the role of IL-10-producing B cells in HIV-1 infection. Compared to uninfected controls, IL-10-producing B cell frequencies were elevated in both blood and sigmoid colon during the early and chronic phase of untreated HIV-1 infection. Ex vivo IL-10-producing B cell frequency in early HIV-1 infection directly correlated with viral load. IL-10-producing B cells from HIV-1 infected individuals were enriched in CD19(+)TIM-1(+) B cells and were enriched for specificity to trimeric HIV-1 envelope protein. Anti-retroviral therapy was associated with reduced IL-10-producing B cell frequencies. Treatment of B cells from healthy donors with microbial metabolites and Toll-like receptor (TLR) agonists could induce an IL-10 producing phenotype, suggesting that the elevated bacterial translocation characteristic of HIV-1 infection may promote IL-10-producing B cell development. Similar to regulatory B cells found in mice, IL-10-producing B cells from HIV-1-infected individuals suppressed HIV-1-specific T cell responses in vitro, and this suppression is IL-10-dependent. Also, ex vivo IL-10-producing B cell frequency inversely correlated with contemporaneous ex vivo HIV-1-specific T cell responses. Our findings show that IL-10-producing B cells are induced early in HIV-1 infection, can be HIV-1 specific, and are able to inhibit effective anti-HIV-1 T cell responses. HIV-1 may dysregulate B cells toward Bregs as an immune evasion strategy.
Assuntos
Linfócitos B Reguladores/imunologia , Infecções por HIV/imunologia , Interleucina-10/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos B Reguladores/metabolismo , Infecções por HIV/metabolismo , HIV-1 , Humanos , Evasão da Resposta Imune/imunologia , Linfócitos T/metabolismoRESUMO
OBJECTIVE: To evaluate if systemic murine malarial infection enhances HIV susceptibility through parasite-induced mucosal immune alterations at sites of HIV sexual exposure. BACKGROUND: Malaria and HIV have a high degree of geographical overlap and interact substantially within coinfected individuals. We used a murine model to test the hypothesis that malaria might also enhance HIV susceptibility at mucosal sites of HIV sexual exposure. METHODS: Female C57/BL6 mice were infected with Plasmodium chabaudi malaria using a standardized protocol. Blood, gastrointestinal tissues, upper and lower genital tract tissues, and iliac lymph nodes were sampled 10 days postinfection, and the expression of putative HIV susceptibility and immune activation markers on T cells was assessed by flow cytometry. RESULTS: P. chabaudi malaria increased expression of mucosal homing integrin α4ß7 on blood CD4 and CD8 T cells, and these α4ß7 T cells had significantly increased co-expression of both CCR5 and CD38. In addition, malaria increased expression of the HIV co-receptor CCR5 on CD4 T cells from the genital tract and gut mucosa as well as mucosal T-cell expression of the immune activation markers CD38, Major Histocompatibility Complex -II (MHC-II) and CD69. CONCLUSIONS: Systemic murine malarial infection induced substantial upregulation of the mucosal homing integrin α4ß7 in blood as well as gut and genital mucosal T-cell immune activation and HIV co-receptor expression. Human studies are required to confirm these murine findings and to examine whether malarial infection enhances the sexual acquisition of HIV.
Assuntos
Suscetibilidade a Doenças , Trato Gastrointestinal/imunologia , Genitália/imunologia , Infecções por HIV/imunologia , Imunidade nas Mucosas , Malária/imunologia , Plasmodium chabaudi/imunologia , Animais , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Ativação Linfocitária , Malária/complicações , Camundongos , Camundongos Endogâmicos C57BL , Receptores de HIV/biossíntese , Linfócitos T/imunologiaRESUMO
The use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) has gained global attention as a promising HIV prevention strategy in men who have sex with men. Permeability of these agents in the rectal mucosa may be partially regulated by interactions with drug efflux transporters, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and/or breast cancer resistance protein (BCRP). The objective of this work was to investigate the expression of drug efflux transporters in recto-sigmoid colon tissues of HIV-infected and uninfected men, and evaluate the association of ART and/or HIV infection with drug transporter expression. MDR1/P-gp, MRPs (1-4) and BCRP mRNA and protein expression were detected in sigmoid colon biopsies of HIV-uninfected individuals. Biopsies from HIV-infected, ART-naïve participants revealed a significant downregulation of P-gp and MRP2 protein levels compared to HIV-uninfected individuals. Biopsies from HIV-infected ART-treated patients showed 1.9-fold higher P-gp protein expression and 1.5-fold higher MRP2 protein expression compared to the ones obtained from the HIV-infected ART-naïve patients. This is a first report demonstrating that HIV infection or ART could alter expression of drug efflux transporters in gut mucosa which in turn could affect the permeability of PrEP antiretroviral agents across this barrier, a highly vulnerable site of HIV transmission.
Assuntos
Antirretrovirais/farmacologia , Colo Sigmoide/metabolismo , Infecções por HIV/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Adulto , Idoso , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Colo Sigmoide/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Contagem de Linfócitos , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Carga Viral , Adulto JovemRESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Viremia/tratamento farmacológico , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Doenças Assintomáticas , Relação CD4-CD8 , Linfócitos T CD4-Positivos/virologia , DNA Viral/sangue , DNA Viral/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Quimioterapia Combinada , Emtricitabina , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Imunidade Inata , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêutico , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Raltegravir Potássico , Tenofovir , Viremia/imunologia , Replicação ViralRESUMO
Mucosal Th17 cells maintain the gut epithelial barrier and prevent invasion by luminal bacteria through a delicate balance of immunosuppressive and proinflammatory functions. HIV infection is characterized by mucosal Th17 depletion, microbial translocation, and immune activation. Therefore, we assessed the function of blood and sigmoid Th17 cells during both early and chronic HIV infection, as well as the impact of short- and long-term antiretroviral therapy. Th17 cells were defined as IL-17a(+) CD4 T cells, and their functional capacity was assessed by the coproduction of the inflammatory cytokines IL-22, TNF-α, and IFN-γ, as well as the immunoregulatory cytokine IL-10. Gut Th17 cells had a much greater capacity to produce proinflammatory cytokines than did those from the blood, but this capacity was dramatically reduced from the earliest stages of HIV infection. Immunoregulatory skewing of mucosal Th17 cell function, characterized by an increased IL-10/TNF-α ratio, was uniquely seen during early HIV infection and was independently associated with reduced systemic immune activation. Antiretroviral therapy rapidly restored mucosal Th17 cell numbers; however, normalization of mucosal Th17 function, microbial translocation, and mucosal/systemic immune activation was much delayed. These findings emphasize that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefit.
Assuntos
Infecções por HIV/imunologia , Mucosa Intestinal/imunologia , Células Th17/imunologia , Adulto , Antirretrovirais/uso terapêutico , Feminino , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Highly active antiretroviral therapy (HAART) dramatically reduces plasma HIV-1 viremia. However, despite completely suppressive HAART, it has been suggested that low-levels of viral replication may persist in the gut mucosa and elsewhere in individuals on long-term HAART. OBJECTIVE: We conducted a double-blind randomized, placebo-controlled trial evaluating whether intensification of HAART in long-term virologically suppressed individuals with raltegravir is associated with a reduction in the level of proviral HIV-1 DNA in CD4(+) T cells in blood and the sigmoid colon (gut). METHODS: Long-term (>4 years) virologically suppressed HIV-infected individuals on standard HAART were randomized 1â:â1 in a double-blind fashion to receive raltegravir (400 âmg twice/day) or placebo for 48 weeks. After week 48, all participants were treated with raltegravir to week 96. Blood and sigmoid biopsies were sampled and the frequency of CD4(+) T cells carrying HIV-1 proviral DNA was determined. RESULTS: Twenty-four study patients were recruited. At 48 weeks, no difference was apparent between participants receiving raltegravir or placebo in blood HIV-1 proviral levels (Pâ=â0.62), CD4(+) T-cell counts (Pâ=â0.25) and gut proviral loads (Pâ=â0.74). Similarly, prolonged raltegravir intensification up to week 96 had no further effect on both blood and gut HIV-1 proviral loads and blood CD4(+) T-cell counts. CONCLUSION: In long-term virologically suppressed patients on standard HAART, intensification with raltegravir did not result in further decay of CD4(+) T cells carrying HIV-1 proviral DNA in either the blood or gut after 48 or 96 weeks of therapy, or in any increase in CD4(+) T-cell counts.
Assuntos
Fármacos Anti-HIV/administração & dosagem , DNA Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Provírus/efeitos dos fármacos , Pirrolidinonas/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , DNA Viral/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Mucosa Intestinal/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Provírus/genética , Raltegravir Potássico , Carga Viral , Viremia/tratamento farmacológico , Viremia/virologiaRESUMO
Interleukin 17 (IL-17) is a central cytokine implicated in inflammation and antimicrobial defense. After infection, both innate and adaptive IL-17 responses have been reported, but the type of cells involved in innate IL-17 induction, as well as their contribution to in vivo responses, are poorly understood. Here we found that Citrobacter and Salmonella infection triggered early IL-17 production, which was crucial for host defense and was mediated by CD4(+) T helper cells. Enteric innate T helper type 17 (iT(H)17) responses occurred principally in the cecum, were dependent on the Nod-like receptors Nod1 and Nod2, required IL-6 induction and were associated with a decrease in mucosal CD103(+) dendritic cells. Moreover, imprinting by the intestinal microbiota was fully required for the generation of iT(H)17 responses. Together, these results identify the Nod-iT(H)17 axis as a central element in controlling enteric pathogens, which may implicate Nod-driven iT(H)17 responses in the development of inflammatory bowel diseases.
Assuntos
Intestinos/microbiologia , Células Th17/imunologia , Animais , Citrobacter rodentium/imunologia , Colite/imunologia , Colite/microbiologia , Infecções por Enterobacteriaceae/imunologia , Feminino , Imunidade Inata/imunologia , Interleucina-17/imunologia , Interleucina-6/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/imunologia , Masculino , Camundongos , Proteína Adaptadora de Sinalização NOD1/imunologia , Proteína Adaptadora de Sinalização NOD2/imunologia , Salmonelose Animal/imunologia , Salmonella typhimurium/imunologiaRESUMO
OBJECTIVE: Th17 cells play an important role in mucosal defence and repair and are highly susceptible to infection by HIV. Antiretroviral therapy (ART) suppresses HIV viremia and can restore CD4(+) numbers in the blood and gastrointestinal mucosa, but the resolution of systemic inflammation and gut microbial translocation is often incomplete. We hypothesized that this might relate to persistent dysregulation of gut CD4(+) Th17 subsets. METHODS: Blood and sigmoid biopsies were collected from HIV-uninfected men, chronically HIV-infected, ART-naive men, and men on effective ART for more than 4 years. Sigmoid provirus levels were assayed blind to participant status, as were CD4(+) Th17 subsets, systemic markers of microbial translocation, and cellular immune activation. RESULTS: There was minimal CD4(+) Th17 dysregulation in the blood until later stage HIV infection, but gastrointestinal Th17 depletion was apparent much earlier, along with increased plasma markers of microbial translocation. Plasma lipopolysaccharide (LPS) remained elevated despite overall normalization of sigmoid Th17 populations on long-term ART, although there was considerable interindividual variability in Th17 reconstitution. An inverse correlation was observed between plasma LPS levels and gut Th17 frequencies, and higher plasma LPS levels correlated with an increased gut HIV proviral reservoir. CONCLUSION: Sigmoid Th17 populations were preferentially depleted during HIV infection. Despite overall CD4(+) T-cell reconstitution, sigmoid Th17 frequencies after long-term ART were heterogeneous and higher frequencies were correlated with reduced microbial translocation.
Assuntos
Translocação Bacteriana/imunologia , Colo Sigmoide/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Mucosa Intestinal/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Células Th17/imunologia , Adulto , Animais , Linfócitos T CD4-Positivos/imunologia , Chlorocebus aethiops , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Masculino , Pessoa de Meia-Idade , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/patogenicidadeRESUMO
Conventional therapies for the treatment of inflammatory bowel disease (IBD) have demonstrated limited efficacy and potential toxicity; therefore, there is a need for novel therapies that can safely and effectively treat IBD. Recent evidence has indicated that amino acids may play a role in maintaining gut health. L-tryptophan has been shown to reduce oxidative stress and improve neurological states. The objective of this study was to assess the therapeutic effects of L-tryptophan in a porcine model of dextran sodium sulfate (DSS)-induced colitis. DSS was administered to piglets via intragastric catheter for 5 days followed by tryptophan administration at 80% of the daily recommended intake. The severity of colitis was assessed macroscopically and histopathologically, and intestinal permeability was monitored in vivo by D-mannitol analysis. The effect of tryptophan on the local expression of key mediators of inflammation and IBD pathogenesis was examined at the protein and gene expression levels. Supplementation with tryptophan ameliorated clinical symptoms and improved weight gain to feed intake conversion ratios. Histological scores and measurements were also improved, and gut permeability was notably reduced in tryptophan-supplemented animals. Moreover, tryptophan reduced the expression of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, interferon (IFN)-gamma, IL-12p40, IL-1beta and IL-17, as well as IL-8 and intracellular adhesion molecule-1, and resulted in increased expression of apoptosis initiators caspase-8 and Bax. These results demonstrate that L-tryptophan supplementation can reduce inflammation and enhance the rate of recovery in DSS-induced colitis and may be an effective immunomodulating agent for the treatment of IBD.