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[This corrects the article DOI: 10.1371/journal.ppat.1005381.].
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Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.
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Antagonistas de los Receptores CCR5/administración & dosificación , Infecciones por VIH/inmunología , Inhibidores de Integrasa VIH/administración & dosificación , Inmunidad Mucosa/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/administración & dosificación , Cromatografía Líquida de Alta Presión , Ciclohexanos/administración & dosificación , Ciclopropanos , Combinación de Medicamentos , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/administración & dosificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Infecciones por VIH/tratamiento farmacológico , Humanos , Activación de Linfocitos/efectos de los fármacos , Masculino , Maraviroc , Proyectos Piloto , Raltegravir Potásico/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Triazoles/administración & dosificaciónRESUMEN
A nested case-cohort study was performed in participants of a clinical trial of first-line human immunodeficiency virus treatments to investigate plasma biomarkers of inflammation and microbial translocation for their association with immune reconstitution inflammatory syndrome (IRIS). Fifty-one of 1452 participants with baseline CD4 count <350 cells/µL developed IRIS. Plasma from 51 IRIS cases, including 6 stratified by preenrollment CD4 count ≤200 cells/µL, were analyzed and compared to 94 non-IRIS controls. At baseline, CXCL10, lipopolysaccharide, soluble CD14, 16S ribosomal DNA, and interferon-α2 were associated with greater risk of IRIS. Systemic inflammation through persistent monocyte activation and microbial translocation appear to be important in IRIS pathogenesis.
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Fármacos Anti-VIH/uso terapéutico , Biomarcadores/sangre , Citocinas/sangre , Infecciones por VIH/tratamiento farmacológico , Síndrome Inflamatorio de Reconstitución Inmune/sangre , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Translocación Genética/inmunología , Estudios de Cohortes , HumanosRESUMEN
Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.
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Benzoxazinas/uso terapéutico , Ciclohexanos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Tejido Linfoide/efectos de los fármacos , Raltegravir Potásico/uso terapéutico , Triazoles/uso terapéutico , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/administración & dosificación , Ciclohexanos/administración & dosificación , Ciclopropanos , ADN Viral , Duodeno/efectos de los fármacos , Duodeno/metabolismo , Femenino , Humanos , Tejido Linfoide/metabolismo , Masculino , Maraviroc , ARN Viral , Raltegravir Potásico/administración & dosificación , Recto/efectos de los fármacos , Recto/metabolismo , Triazoles/administración & dosificaciónRESUMEN
BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.
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Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/mortalidad , Adulto , Femenino , Humanos , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
OBJECTIVE: Mechanisms underlying the cardiovascular risk of lipoprotein(a) are poorly understood. We investigated the relationship of apolipoprotein(a) (apo(a)) size, lipoprotein(a), and allele-specific apo(a) levels with HIV disease activity parameters in a biethnic population. METHODS AND RESULTS: Lipoprotein(a) and allele-specific apo(a) levels were determined in 139 white and 168 black HIV-positive patients. Plasma HIV RNA viral load and CD4+ T-cell count were used as surrogates for disease activity. Lipoprotein(a) and allele-specific apo(a) levels were higher in blacks than whites (for both P<0.001). Apo(a) allele size distribution was similar between the 2 ethnic groups, with a median apo(a) size of 28 kringle 4 repeats. Allele-specific apo(a) levels were positively associated with CD4+ T-cell count (P=0.027) and negatively with plasma HIV RNA viral load (P<0.001). Further, allele-specific apo(a) levels associated with smaller (<28 kringle 4) atherogenic apo(a) sizes were higher in subjects with CD4+ T-cell counts of ≥350 (P=0.002). CONCLUSIONS: Allele-specific apo(a) levels were higher in subjects with high CD4+ T-cell count or low plasma HIV RNA viral load. The findings suggest that HIV disease activity reduced allele-specific apo(a) levels. Higher allele-specific apo(a) levels associated with atherogenic small apo(a) sizes might contribute to increased cardiovascular risk in HIV-positive subjects with improved disease status.
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Apoproteína(a)/sangre , Infecciones por VIH/sangre , Lipoproteína(a)/sangre , Adulto , Negro o Afroamericano/genética , Apoproteína(a)/genética , Biomarcadores/sangre , Recuento de Linfocito CD4 , California/epidemiología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etnología , Enfermedades Cardiovasculares/virología , Estudios Transversales , Femenino , VIH/genética , VIH/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Infecciones por VIH/etnología , Infecciones por VIH/virología , Humanos , Lipoproteína(a)/genética , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Pronóstico , ARN Viral/sangre , Factores de Riesgo , Carga Viral , Población Blanca/legislación & jurisprudenciaRESUMEN
BACKGROUND: HIV-1 coreceptor tropism testing is used to evaluate eligibility for CCR5 antagonist therapy. However, HIV-1 RNA-based tests are not suitable for virologically suppressed patients, therefore the use of proviral DNA tropism testing has been investigated. We describe a novel proviral DNA-based genotypic tropism assay and compare its performance to that of a sensitive HIV-1 RNA-based genotypic test. METHODS: Tropism was determined using HIV-1 plasma RNA and proviral DNA from 42 paired samples from patients with plasma viral loads ≥1000 HIV-1 RNA copies/mL. Proviral DNA sample types included whole blood, separated peripheral blood mononuclear cells resuspended in phosphate-buffered saline and peripheral blood mononuclear cells resuspended in spun plasma. The HIV-1 envelope V3 region was PCR-amplified, sequenced in triplicate, and analyzed for tropism with the geno2pheno algorithm using a 10% false-positive rate (FPR). RESULTS: Amplicons were obtained from proviral DNA and plasma RNA in 41/42 samples. Tropism predictions were highly concordant (93%-98%) between proviral DNA and plasma RNA, regardless of the proviral DNA isolation method. Non-R5 proviral DNA results were obtained for 100% of patients with detectable non-R5 plasma HIV-1 RNA results. Geno2pheno FPRs for proviral DNA and plasma RNA were highly correlated (Spearman rho = 0.86). CONCLUSIONS: Our findings demonstrate that proviral DNA tropism determinations from whole blood or peripheral blood mononuclear cells were highly concordant with plasma HIV-1 RNA tropism determinations. This assay may be useful for screening virologically suppressed patients for CCR5-antagonist eligibility and for research purposes.
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HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1(-/-) IL2rγ(-/-) knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34(+) HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34(+) cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4(+) cell levels and a selective survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.
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Tratamiento Basado en Trasplante de Células y Tejidos , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Células Madre Hematopoyéticas/inmunología , Transducción Genética , Animales , Antígenos CD34/inmunología , Terapia Genética , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Infecciones por VIH/genética , VIH-1/fisiología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/virología , Humanos , Lentivirus/genética , Lentivirus/metabolismo , RatonesRESUMEN
BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus-infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear. METHODS: We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels. RESULTS: Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-γ, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-γ and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-γ at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS. CONCLUSIONS: Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.
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Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Citocinas/sangre , Infecciones por VIH/tratamiento farmacológico , Síndrome Inflamatorio de Reconstitución Inmune/metabolismo , Interleucina-8/sangre , Adulto , Biomarcadores , Estudios de Casos y Controles , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Modelos Logísticos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1-infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = -0.7; P < .05) with virological response. The strength of peginterferon alfa-2a-induced IFIG response significantly correlated with declines in HIV load during treatment (r(2) = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a-treated patients with HIV infection.
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Antivirales/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , VIH-1/patogenicidad , Interacciones Huésped-Patógeno/genética , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Humanos , Leucocitos Mononucleares/metabolismo , ARN Viral/genética , ARN Viral/aislamiento & purificación , Proteínas Recombinantes/administración & dosificación , Carga ViralRESUMEN
Gut-associated lymphoid tissue (GALT) is a major site of HIV replication and CD4(+) T cell depletion. Furthermore, microbial translocation facilitated by mucosal damage likely contributes to the generalized immune activation observed in HIV infection. Regulatory T cells (Treg) help maintain homeostasis and suppress harmful immune activation during infection; however, in the case of persistent viral infections such as HIV, their role is less clear. Although a number of studies have examined Treg in blood during chronic infection, few have explored Treg in the gastrointestinal mucosa. For this study, paired blood and rectal biopsy samples were obtained from 12 HIV noncontrollers (viral load of >10,000 copies/ml plasma), 10 HIV controllers (viral load of <500 copies/ml plasma for more than 5 years), and 12 HIV seronegative control subjects. Noncontrollers had significantly higher percentages of Treg in rectal mononuclear cells (RMNC), but not in blood, compared to seronegative subjects (P = 0.001) or HIV controllers (P = 0.002). Mucosal Treg positively correlated with viral load (P = 0.01) and expression of immune activation markers by CD4(+) (P = 0.01) and CD8(+) (P = 0.07) T cells. Suppression assays indicated that mucosal and peripheral Treg of noncontrollers and controllers maintained their capacity to suppress non-Treg proliferation to a similar extent as Treg from seronegative subjects. Together, these findings reveal that rather than experiencing depletion, mucosal Treg frequency is enhanced during chronic HIV infection and is positively correlated with viral load and immune activation. Moreover, mucosal Treg maintain their suppressive ability during chronic HIV infection, potentially contributing to diminished HIV-specific T cell responses and viral persistence.
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Infecciones por VIH/inmunología , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Recto/inmunología , Linfocitos T Reguladores/inmunología , Antígenos CD/análisis , Sangre/inmunología , Sangre/virología , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/inmunología , Mucosa Intestinal/virología , Recto/virología , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/química , Carga ViralRESUMEN
Previous studies have suggested that polyfunctional mucosal CD8(+) T-cell responses may be a correlate of protection in HIV controllers. Mucosal T-cell breadth and/or specificity may also contribute to defining protective responses. In this study, rectal CD8(+) T-cell responses to HIV Gag, Env, and Nef were mapped at the peptide level in four subject groups: elite controllers (n = 16; viral load [VL], <75 copies/ml), viremic controllers (n = 14; VL, 75 to 2,000 copies/ml), noncontrollers (n = 14; VL, >10,000 copies/ml), and antiretroviral-drug-treated subjects (n = 8; VL, <75 copies/ml). In all subject groups, immunodominant CD8(+) T-cell responses were generally shared by blood and mucosa, although there were exceptions. In HIV controllers, responses to HLA-B27- and HLA-B57-restricted epitopes were common to both tissues, and their magnitude (in spot-forming cells [SFC] per million) was significantly greater than those of responses restricted by other alleles. Furthermore, peptides recognized by T cells in both blood and rectal mucosa, termed "concordant," elicited higher median numbers of SFC than discordant responses. In magnitude as well as breadth, HIV Gag-specific responses, particularly those targeting p24 and p7, dominated in controllers. Responses in noncontrollers were more evenly distributed among epitopes in Gag, Env, and Nef. Viremic controllers showed significantly broader mucosal Gag-specific responses than other groups. Taken together, these findings demonstrate that (i) Gag-specific responses dominate in mucosal tissues of HIV controllers; (ii) there is extensive overlap between CD8(+) T cells in blood and mucosal tissues, with responses to immunodominant epitopes generally shared by both sites; and (iii) mucosal T-cell response breadth alone cannot account for immune control.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Sobrevivientes de VIH a Largo Plazo , VIH-1 , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Terapia Antirretroviral Altamente Activa , Femenino , Antígenos VIH , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , VIH-1/inmunología , Antígenos HLA-B , Antígeno HLA-B27 , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Mucosa , Epítopos Inmunodominantes , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Masculino , Recto/inmunología , Recto/virología , Carga Viral , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4+ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8+ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4+ T cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the rectal mucosa of 28 "controllers" (viral load [VL] of <2,000 copies/ml), 14 "noncontrollers" (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had higher-magnitude Gag-specific mucosal CD4+ T-cell responses than individuals on HAART (P<0.05), as measured by their ability to produce gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 1ß (MIP-1ß). The frequency of polyfunctional mucosal CD4+ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P<0.05). Controllers with the strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4+ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4+ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8+ T-cell response (Spearman's r=0.43, P=0.005), suggesting that increased CD4+ T-cell "help" may be important in maintaining strong CD8+ T-cell responses in the gut of HIV controllers.
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Linfocitos T CD4-Positivos/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH/inmunología , Antígenos HLA-DQ/inmunología , Mucosa Intestinal/inmunología , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Citocinas/biosíntesis , Productos del Gen gag/inmunología , Cadenas beta de HLA-DQ , Antígenos HLA-DR , Cadenas HLA-DRB1 , Mucosa Intestinal/virología , FenotipoRESUMEN
There exists a unique group of persons who are able to durably control HIV in the absence of therapy. The mechanisms of control in these persons remain poorly defined. In this study, we examined CD8(+) T-cell responses in blood and rectal mucosa from 17 "elite controllers" (viral load < 75 copies/mL), 11 "viremic controllers" (75-2000 copies/mL), 14 noncontrollers (> 10,000 copies/mL), and 10 antiretroviral-treated persons (< 75 copies/mL). Production of interferon-gamma, interleukin-2, tumor necrosis factor-alpha, macrophage inflammatory protein-1 beta, and CD107a by CD8(+) T cells in response to HIV-1 Gag stimulation was measured using flow cytometry. Our hypothesis was that "polyfunctional" T cells producing multiple antiviral factors would be most abundant in mucosal tissues of HIV controllers. Mucosal CD8(+) T-cell responses were significantly stronger and more complex in controllers than in antiretroviral-suppressed persons (P = .0004). The frequency of 4-function responses in rectal mucosa was higher in controllers than in noncontrollers and patients on therapy (P < .0001). Mucosal responses in controllers were frequently stronger and more complex than blood responses. These findings demonstrate that many controllers mount strong, complex HIV-specific T-cell responses in rectal mucosa. These responses may play an important role in mucosal immune surveillance, as suggested by their relative enrichment among persons who control HIV in the absence of therapy.
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Infecciones por VIH/inmunología , VIH-1/inmunología , Biopsia , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Recuento de Células , Quimiocina CCL4/biosíntesis , Quimiocina CCL4/inmunología , Femenino , Productos del Gen gag/inmunología , Genotipo , Infecciones por VIH/patología , Infecciones por VIH/cirugía , Salud , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunidad Mucosa/inmunología , Interferón gamma/inmunología , Masculino , Recto/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: To identify inflammatory pathways that may contribute to the pathogenesis of human immunodeficiency virus (HIV) disease, we explored associations between AIDS or death and different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors (sTNFRs) and ligands, interleukin (IL)-6, and CD8 T cell activation, in individuals treated with highly active antiretroviral therapy (HAART). METHODS: A case-control study of subjects in AIDS Clinical Trials Group (ACTG) protocols 384 and 5015, who were matched according to the CD4 cell count and plasma viral load at baseline, was performed using conditional logistic regression. RESULTS: Higher pretreatment concentrations of sTNFR-1, sCD27, sCD40L, and plasma IL-6 were associated with a new AIDS-defining illness or death in separate models adjusted for age, sex, hemoglobin, and the latest CD4 cell counts. In additional models that excluded case patients with opportunistic infections, sTNFR-1, sCD27, and sCD40L were each associated with a new AIDS-defining malignancy or death that developed at a median of 51 weeks after initiation of HAART, by which time the majority of subjects had a CD4 cell count of >200 cells/cm(3) and had achieved a plasma viral load of <50 copies/mL. CONCLUSION: These data are compatible with a model in which these soluble inflammatory markers identify pathways that may contribute to the pathogenesis of HIV disease progression, pathways that might not be a direct consequence of ongoing HIV type 1 replication.
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Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Interleucina-6/sangre , Receptores del Factor de Necrosis Tumoral/sangre , Adulto , Biomarcadores , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carga ViralRESUMEN
BACKGROUND: To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. METHODS: Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. RESULTS: Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). CONCLUSION: Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , 2',5'-Oligoadenilato Sintetasa/metabolismo , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Recuento de Linfocito CD4 , Perfilación de la Expresión Génica , Infecciones por VIH/virología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacocinética , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , ARN Viral/sangre , Proteínas Recombinantes , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. METHODS: Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941. FINDINGS: 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. INTERPRETATION: Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. FUNDING: Merck.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Pirrolidinonas/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Alquinos , Análisis de Varianza , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/uso terapéutico , Ciclopropanos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Emtricitabina , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , Humanos , Masculino , Organofosfonatos/uso terapéutico , Pronóstico , Pirrolidinonas/farmacología , ARN Viral/efectos de los fármacos , Raltegravir Potásico , Seguridad , Tenofovir , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks. RESULTS: The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm3 at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed. CONCLUSIONS: Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease. TRIAL REGISTRATION: A5051 ClinicalTrials.gov Identifier: NCT00000923.
RESUMEN
BACKGROUND: Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized. METHODS: Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113. RESULTS: Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico
, Síndrome de Inmunodeficiencia Adquirida/inmunología
, Terapia Antirretroviral Altamente Activa
, Subgrupos de Linfocitos T/inmunología
, Adulto
, Linfocitos B/inmunología
, Recuento de Linfocito CD4
, Relación CD4-CD8
, Femenino
, Humanos
, Células Asesinas Naturales/inmunología
, Masculino
, Persona de Mediana Edad