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1.
Cell ; 184(15): 3899-3914.e16, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34237254

RESUMEN

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.


Asunto(s)
Microbioma Gastrointestinal , Infecciones por VIH/inmunología , Infecciones por VIH/microbiología , Terapia Antirretroviral Altamente Activa , Biodiversidad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocinas/sangre , Estudios de Cohortes , Glucólisis , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Inflamación/genética , Inflamación/patología , Mitocondrias/metabolismo , Monocitos/metabolismo , Ácidos Nucleicos/sangre , Análisis de Componente Principal , Serratia/fisiología , Células TH1/inmunología , Células Th2/inmunología , Transcripción Genética , Uganda , Carga Viral/inmunología
2.
J Virol ; 98(10): e0128824, 2024 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-39264207

RESUMEN

SARS-CoV-2 infects via the respiratory tract, but COVID-19 includes an array of non-respiratory symptoms, among them gastrointestinal (GI) manifestations such as vomiting and diarrhea. Here we investigated the GI pathology of SARS-CoV-2 infections in rhesus macaques and humans. Macaques experienced mild infection with USA-WA1/2020 and shed viral RNA in the respiratory tract and stool, including subgenomic RNA indicative of replication in the GI tract. Intestinal immune cell populations were disturbed, with significantly fewer proliferating (Ki67+) jejunal B cells in SARS-CoV-2-infected macaques than uninfected ones. Modest translocation of bacteria/bacterial antigen was observed across the colonic epithelium, with a corresponding significant increase in plasma soluble CD14 (sCD14) that may be induced by LPS. Human plasma demonstrated significant decreases in interleukin (IL)-6 and sCD14 upon recovery from COVID-19, suggesting resolution of inflammation and response to translocated bacteria. sCD14 significantly positively correlated with zonulin, an indicator of gut barrier integrity, and IL-6. These results demonstrate that GI perturbations such as microbial translocation can occur in even mild SARS-CoV-2 infections and may contribute to the COVID-19 inflammatory state.IMPORTANCEThis study investigates gastrointestinal (GI) barrier disruption in SARS-CoV-2 infections and how it may contribute to disease. We observed bacteria or bacterial products crossing from the colon interior (the lumen) to the lamina propria during SARS-CoV-2 infection in macaques. Bacteria/bacterial products are tolerated in the lumen but may induce immune responses if they translocate to the lamina propria. We also observed a significant increase in soluble CD14, which is associated with an immune response to bacterial products. In addition, we observed that humans recovering from COVID-19 experienced a significant decrease in soluble CD14, as well as the inflammatory marker interleukin (IL)-6. IL-6 and sCD14 correlated significantly across macaque and human samples. These findings suggest that SARS-CoV-2 infection results in GI barrier disruption that permits microbial translocation and a corresponding immune response. These findings could aid in developing interventions to improve COVID-19 patient outcomes.


Asunto(s)
Traslocación Bacteriana , COVID-19 , Interleucina-6 , Receptores de Lipopolisacáridos , Macaca mulatta , SARS-CoV-2 , Animales , COVID-19/inmunología , COVID-19/virología , COVID-19/microbiología , Humanos , SARS-CoV-2/inmunología , Receptores de Lipopolisacáridos/metabolismo , Interleucina-6/metabolismo , Masculino , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/virología , Tracto Gastrointestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Mucosa Intestinal/metabolismo , Femenino , Haptoglobinas/metabolismo , Linfocitos B/inmunología , Persona de Mediana Edad , Precursores de Proteínas
3.
J Virol ; 93(9)2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30787150

RESUMEN

Among the numerous immunological abnormalities observed in chronically human immunodeficiency virus (HIV)-infected individuals, perturbations in memory CD4 T cells are thought to contribute specifically to disease pathogenesis. Among these, functional imbalances in the frequencies of T regulatory cells (Tregs) and interleukin 17 (IL-17)/IL-22-producing Th cells (Th17/Th22) from mucosal sites and T follicular helper (Tfh) cells in lymph nodes are thought to facilitate specific aspects of disease pathogenesis. However, while preferential infection of Tfh cells is widely thought to create an important viral reservoir in an immunologically privileged site in vivo, whether immunological perturbations among memory CD4 T cell populations are attributable to their relative infectivity by the virus in vivo is unclear. Here we studied peripheral blood and lymphoid tissues from antiretroviral (ARV)-treated and ARV-naive Asian macaques and isolated functionally defined populations of memory CD4 T cells. We then assessed the degree to which these populations were infected by simian immunodeficiency virus (SIV) in vivo, to determine whether particular functionally identified populations of memory CD4 T cells were preferentially infected by the virus. We found that SIV did not preferentially infect Th17 cells, compared to Th1 cells, Th2 cells, or Tregs. Moreover, Th17 cells contributed proportionately to the total pool of infected cells. Taken together, our data suggest that, although Tfh cells are more prone to harbor viral DNA, other functionally polarized cells are equally infected by the virus in vivo and Th17 cells are not preferentially infected.IMPORTANCE Functional perturbations of memory CD4 T cells have been suggested to underlie important aspects of HIV disease progression. However, the mechanisms underlying these perturbations remain unclear. Using a nonhuman primate model of HIV, we show that SIV infects functionally defined populations of memory CD4 T cells equally in different anatomic sites. Thus, preferential infection by the virus is unlikely to cause functional perturbations.


Asunto(s)
ADN Viral/inmunología , Memoria Inmunológica/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Antirretrovirales/farmacología , Macaca mulatta , Macaca nemestrina , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Linfocitos T Colaboradores-Inductores/virología
4.
J Virol ; 93(18)2019 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-31270225

RESUMEN

Gastrointestinal (GI) immune system competency is dependent upon interactions with commensal microbiota, which can be influenced by wide-ranging pharmacologic interventions. In simian immunodeficiency virus (SIV)-infected Asian macaque models of human immunodeficiency virus (HIV) infection, we previously noted that initiation of antiretroviral therapy (ART) is associated with a specific imbalance (dysbiosis) of the composition of the intestinal bacteriome. To determine if ART itself might contribute to dysbiosis or immune dysfunction, we treated healthy rhesus macaques with protease, integrase, or reverse transcriptase inhibitors for 1 to 2 or for 5 to 6 weeks and evaluated intestinal immune function and the composition of the fecal bacterial microbiome. We observed that individual antiretrovirals (ARVs) modestly altered intestinal T-cell proinflammatory responses without disturbing total or activated T-cell frequencies. Moreover, we observed transient disruptions in bacterial diversity coupled with perturbations in the relative frequencies of bacterial communities. Shifts in specific bacterial frequencies were not persistent posttreatment, however, with individual taxa showing only isolated associations with T-cell proinflammatory responses. Our findings suggest that intestinal bacterial instability and modest immunological alterations can result from ART itself. These data could lead to therapeutic interventions which stabilize the microbiome in individuals prescribed ART.IMPORTANCE Dysbiosis of the fecal microbiome is a common feature observed in ARV-treated people living with HIV. The degree to which HIV infection itself causes this dysbiosis remains unclear. Here, we demonstrate that medications used to treat HIV infection can influence the composition of the GI tract immune responses and its microbiome in the nonhuman primate SIV model.


Asunto(s)
Disbiosis/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/inmunología , Animales , Antirretrovirales/efectos adversos , Antirretrovirales/farmacología , Modelos Animales de Enfermedad , Disbiosis/virología , Femenino , Intestinos/inmunología , Intestinos/microbiología , Activación de Linfocitos/efectos de los fármacos , Macaca mulatta/metabolismo , Masculino , Microbiota/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T/inmunología
5.
Mucosal Immunol ; 17(5): 1089-1101, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39089468

RESUMEN

Microbial translocation is a significant contributor to chronic inflammation in people living with HIV (PLWH) and is associated with increased mortality and morbidity in individuals treated for long periods with antiretrovirals. The use of therapeutics to treat microbial translocation has yielded mixed effects, in part, because the species and mechanisms contributing to translocation in HIV remain incompletely characterized. To characterize translocating bacteria, we cultured translocators from chronically SIV-infected rhesus macaques. Proteomic profiling of these bacteria identified cytosine-specific methyltransferases as a common feature and therefore, a potential driver of translocation. Treatment of translocating bacteria with the cytosine methyltransferase inhibitor decitabine significantly impaired growth for several species in vitro. In rhesus macaques, oral treatment with decitabine led to some transient decreases in translocator taxa in the gut microbiome. These data provide mechanistic insight into bacterial translocation in lentiviral infection and explore a novel therapeutic intervention that may improve the prognosis of PLWH.


Asunto(s)
Traslocación Bacteriana , Microbioma Gastrointestinal , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Humanos , Bacterias , Decitabina/farmacología , Proteómica
6.
Microbiol Spectr ; 11(1): e0213922, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36475838

RESUMEN

The bacterial component of the gastrointestinal tract microbiome is comprised of hundreds of species, the majority of which live in symbiosis with the host. The bacterial microbiome is influenced by host diet and disease history, and host genetics may additionally play a role. To understand the degree to which host genetics shapes the gastrointestinal tract microbiome, we studied fecal microbiomes in 4 species of nonhuman primates (NHPs) held in separate facilities but fed the same base diet. These animals include Chlorocebus pygerythrus, Chlorocebus sabaeus, Macaca mulatta, and Macaca nemestrina. We also followed gastrointestinal tract microbiome composition in 20 Macaca mulatta (rhesus macaques [RMs]) as they transitioned from an outdoor to indoor environment and compared 6 Chlorocebus pygerythrus monkeys that made the outdoor to indoor transition to their 9 captive-born offspring. We found that genetics can influence microbiome composition, with animals of different genera (Chlorocebus versus Macaca) having significantly different gastrointestinal (GI) microbiomes despite controlled diets. Animals within the same genera have more similar microbiomes, although still significantly different, and animals within the same species have even more similar compositions that are not significantly different. Significant differences were also not observed between wild-born and captive-born Chlorocebus pygerythrus, while there were significant changes in RMs as they transitioned into captivity. Together, these results suggest that the effects of captivity have a larger impact on the microbiome than other factors we examined within a single NHP species, although host genetics does significantly influence microbiome composition between NHP genera and species. IMPORTANCE Our data point to the degree to which host genetics can influence GI microbiome composition and suggest, within primate species, that individual host genetics is unlikely to significantly alter the microbiome. These data are important for the development of therapeutics aimed at altering the microbiome within populations of genetically disparate members of primate species.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Animales , Chlorocebus aethiops , Microbioma Gastrointestinal/genética , Macaca mulatta , Filogenia , Microbiota/genética , Dieta , ARN Ribosómico 16S/genética
7.
Cell Rep ; 42(1): 112020, 2023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36848230

RESUMEN

Variations in the composition of the intestinal bacterial microbiome correlate with acquisition of some sexually transmitted pathogens. To experimentally assess the contribution of intestinal dysbiosis to rectal lentiviral acquisition, we induce dysbiosis in rhesus macaques (RMs) with the antibiotic vancomycin prior to repeated low-dose intrarectal challenge with simian immunodeficiency virus (SIV) SIVmac239X. Vancomycin administration reduces T helper 17 (TH17) and TH22 frequencies, increases expression of host bacterial sensors and antibacterial peptides, and increases numbers of transmitted-founder (T/F) variants detected upon SIV acquisition. We observe that SIV acquisition does not correlate with measures of dysbiosis but rather associates with perturbations in the host antimicrobial program. These findings establish a functional association between the intestinal microbiome and susceptibility to lentiviral acquisition across the rectal epithelial barrier.


Asunto(s)
Disbiosis , Virus de la Inmunodeficiencia de los Simios , Animales , Macaca mulatta , Vancomicina , Antibacterianos
8.
Sci Rep ; 12(1): 7491, 2022 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-35523797

RESUMEN

Defective gastrointestinal barrier function and, in turn, microbial translocation have been identified as significant contributors to persistent inflammation in antiretroviral (ARV)-treated people living with HIV. Metabolic supplementation of short-chain fatty acids (SCFAs), generally produced by the commensal microbiome, may improve these outcomes. Butyrate is a SCFA that is essential for the development and maintenance of intestinal immunity and has a known role in supporting epithelial integrity. Herein we assessed whether supplementation with the dietary supplement sodium butyrate would improve immune reconstitution and reduce inflammation in ARV-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques. We demonstrate that butyrate supplementation does not significantly improve immune reconstitution, with no differences observed in systemic CD4+ T-cell frequencies, T-cell functionality or immune activation, microbial translocation, or transcriptional regulation. Our findings demonstrate that oral administration of sodium butyrate is insufficient to reduce persistent inflammation and microbial translocation in ARV-treated, SIV-infected macaques, suggesting that this therapeutic may not reduce co-morbidities and co-mortalities in treated people living with HIV.


Asunto(s)
Infecciones por VIH , Reconstitución Inmune , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Ácido Butírico/farmacología , Ácido Butírico/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Macaca mulatta
9.
Microbiol Spectr ; 9(3): e0107421, 2021 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-34756073

RESUMEN

The vaginal microbiome composition in humans is categorized based upon the degree to which one of four species of Lactobacillus is dominant (Lactobacillus crispatus, community state type I [CST I], Lactobacillus gasseri, CST II, Lactobacillus iners, CST III, and Lactobacillus jensenii, CST V). Women with a vaginal microbiome not dominated by one of the four Lactobacillus species tend to have a more diverse microbiome, CST IV. CSTs I, II, III, and V are common in North America and Europe and are associated with lower incidences of some pathogens, such as human immunodeficiency virus (HIV), human papillomavirus (HPV), and Gardnerella vaginalis. As a result, therapeutic interventions to change the composition of the vaginal microbiomes are under development. However, Homo sapiens is the only mammalian species which has high frequencies of Lactobacillus-dominated vaginal microbiomes. Here, we treated female nonhuman primates (NHPs) with regimens of metronidazole and high levels of L. crispatus to determine how well these animals could be colonized with L. crispatus, how this influenced the immunological milieu, and how Lactobacillus treatment influenced or was influenced by the endogenous vaginal microbiome. We find that NHPs can transiently be colonized with L. crispatus, that beta diversity and not the number of doses of L. crispatus or pretreatment with metronidazole predicts subsequent L. crispatus colonization, that L. crispatus does not alter the local immunological milieu, and that the vaginal microbiome composition was resilient, normalizing by 4 weeks after our manipulations. Overall, this study suggests these animals are not amenable to long-term L. crispatus colonization. IMPORTANCE NHPs have proven to be invaluable animal models for the study of many human infectious diseases. The use of NHPs to study the effect of the microbiome on disease transmission and susceptibility is limited due to differences between the native microbiomes of humans and NHPs. In particular, Lactobacillus dominance of the vaginal microbiome is unique to humans and remains an important risk factor in reproductive health. By assessing the extent to which NHPs can be colonized with exogenously applied L. crispatus to resemble a human vaginal microbiome and examining the effects on the vaginal microenvironment, we highlight the utility of NHPs in analysis of vaginal microbiome manipulations in the context of human disease.


Asunto(s)
Chlorocebus aethiops/microbiología , Lactobacillus crispatus/crecimiento & desarrollo , Macaca mulatta/microbiología , Microbiota/genética , Vagina/microbiología , Animales , Antibacterianos/farmacología , Femenino , Humanos , Inflamación/patología , Lactobacillus crispatus/metabolismo , Menstruación/fisiología , Metronidazol/farmacología
10.
Open Forum Infect Dis ; 8(12): ofab550, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34888397

RESUMEN

BACKGROUND: A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function. METHODS: The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample t test with equal variance or the Wilcoxon rank-sum test. For safety, the highest graded adverse events (AEs) were compared between arms using the Fisher exact test. RESULTS: Overall, 93 participants enrolled: 86% male, median age 51 years, median CD4 count 712 cells/mm3. Visbiome ES was safe and well tolerated. There was no difference in mean change in sCD14 from baseline to week 25/26 between placebo (mean change, 92.3 µg/L; 95% CI, -48.5 to 233 µg/L) and Visbiome ES (mean change, 41.0 µg/L; 95% CI, -94.1 to 176.2 µg/L; P=.60). Similarly, no statistically significant differences between arms in inflammatory marker changes were identified. In substudy participants, no statistical differences between arms for change in cellular marker expression or gut permeability were observed (P>.05 for all). The microbiome demonstrated increased probiotic species and a significant decrease in Gammaproteobacteria (P=.044) in the Visbiome ES arm. CONCLUSIONS: Visbiome ES was safe and altered the microbiome but demonstrated no effect on systemic inflammatory markers, pathology, or gut permeability in antiretroviral therapy-treated people with HIV.

11.
Mucosal Immunol ; 14(4): 937-948, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33731830

RESUMEN

Microbial translocation contributes to persistent inflammation in both treated and untreated HIV infection. Although translocation is due in part to a disintegration of the intestinal epithelial barrier, there is a bias towards the translocation of Proteobacteria. We hypothesized that intestinal epithelial microvesicle cargo differs after HIV infection and contributes to biased translocation. We isolated gastrointestinal luminal microvesicles before and after progressive simian immunodeficiency virus (SIV) infection in rhesus macaques and measured miRNA and antimicrobial peptide content. We demonstrate that these microvesicles display decreased miR-28-5p, -484, -584-3p, and -584-5p, and let-7b-3p, as well as increased beta-defensin 1 after SIV infection. We further observed dose-dependent growth sensitivity of commensal Lactobacillus salivarius upon co-culture with isolated microvesicles. Infection-associated microvesicle differences were not mirrored in non-progressively SIV-infected sooty mangabeys. Our findings describe novel alterations of antimicrobial control after progressive SIV infection that influence the growth of translocating bacterial taxa. These studies may lead to the development of novel therapeutics for treating chronic HIV infection, microbial translocation, and inflammation.


Asunto(s)
Traslocación Bacteriana , Disbiosis/etiología , Vesículas Extracelulares/metabolismo , Microbioma Gastrointestinal , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios , Animales , Biomarcadores , Progresión de la Enfermedad , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Macaca mulatta , MicroARNs/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones
12.
JCI Insight ; 5(18)2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32841214

RESUMEN

African green monkeys (AGMs) are natural hosts of SIV that postthymically downregulate CD4 to maintain a large population of CD4-CD8aa+ virus-resistant cells with Th functionality, which can result in AGMs becoming apparently cured of SIVagm infection. To understand the mechanisms of this process, we performed genome-wide transcriptional analysis on T cells induced to downregulate CD4 in vitro from AGMs and closely related patas monkeys and T cells that maintain CD4 expression from rhesus macaques. In T cells that downregulated CD4, pathway analysis revealed an atypical regulation of the DNA methylation machinery, which was reversible when pharmacologically targeted with 5-aza-2 deoxycytidine. This signature was driven largely by the dioxygenase TET3, which became downregulated with loss of CD4 expression. CpG motifs within the AGM CD4 promoter region became methylated during CD4 downregulation in vitro and were stably imprinted in AGM CD4-CD8aa+ T cells sorted directly ex vivo. These results suggest that AGMs use epigenetic mechanisms to durably silence the CD4 gene. Manipulation of these mechanisms could provide avenues for modulating SIV and HIV-1 entry receptor expression in hosts that become progressively infected with SIV, which could lead to novel therapeutic interventions aimed to reduce HIV viremia in vivo.


Asunto(s)
Antígenos CD4/antagonistas & inhibidores , Linfocitos T CD4-Positivos/inmunología , Epigénesis Genética , Regulación de la Expresión Génica , Inmunidad Innata/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Animales , Antígenos CD4/genética , Antígenos CD4/metabolismo , Chlorocebus aethiops , Metilación de ADN , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/genética
13.
Pathog Immun ; 5(1): 68-88, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32426577

RESUMEN

BACKGROUND: Microbial translocation occurs after damage to the structural and/or immunological barrier of the gastrointestinal (GI) tract into circulation. Microbial components that trans-locate from the lumen of the GI tract directly stimulate the immune system and contribute to inflammation. When microbial translocation becomes chronic, the inflammation has detrimental consequences. Given that microbial translocation is an important phenomenon in many diseases, defining biomarkers that reliably reflect microbial translocation is critical. Measurement of systemic microbial products is difficult since: 1) robust assays to measure microbial antigens simultaneously are lacking; 2) confounding factors influence assays used to detect microbial products; and 3) biological clearance mechanisms limit their detection in circulation. Thus, host proteins produced in response to microbial stimulation are used as surrogates for microbial translocation; however, many of these proteins are also produced in response to host proteins expressed by dying cells. METHODS: We measured plasma levels of biomarkers associated with GI tract damage, immune responses to microbial products, and cell-death in people living with HIV before and after antiretroviral administration, and in macaque nonhuman primates before and after SIV infection. RESULTS: Proteins secreted during cellular stress (receptor for advanced glycation endproducts-RAGE and high motility group box 1-HMGB1), which can induce sCD14 production in vitro and in vivo, do not associate with elevated levels of biomarkers associated with microbial translocation in progressively HIV-infected individuals and SIV-infected NHPs. CONCLUSIONS: Bystander cell death and generalized inflammation do not contribute to elevated levels of sCD14 observed in HIV/SIV-infected individuals.

14.
J Clin Invest ; 130(2): 789-798, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-31661461

RESUMEN

CD8+ T cell responses are necessary for immune control of simian immunodeficiency virus (SIV). However, the key parameters that dictate antiviral potency remain elusive, conceivably because most studies to date have been restricted to analyses of circulating CD8+ T cells. We conducted a detailed clonotypic, functional, and phenotypic survey of SIV-specific CD8+ T cells across multiple anatomical sites in chronically infected rhesus macaques with high (>10,000 copies/mL plasma) or low burdens of viral RNA (<10,000 copies/mL plasma). No significant differences in response magnitude were identified across anatomical compartments. Rhesus macaques with low viral loads (VLs) harbored higher frequencies of polyfunctional CXCR5+ SIV-specific CD8+ T cells in various lymphoid tissues and higher proportions of unique Gag-specific CD8+ T cell clonotypes in the mesenteric lymph nodes relative to rhesus macaques with high VLs. In addition, public Gag-specific CD8+ T cell clonotypes were more commonly shared across distinct anatomical sites than the corresponding private clonotypes, which tended to form tissue-specific repertoires, especially in the peripheral blood and the gastrointestinal tract. Collectively, these data suggest that functionality and tissue localization are important determinants of CD8+ T cell-mediated efficacy against SIV.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa , Ganglios Linfáticos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Linfocitos T CD8-positivos/patología , Ganglios Linfáticos/patología , Macaca mulatta , Mesenterio/inmunología , Mesenterio/patología , Membrana Mucosa , Especificidad de Órganos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología
15.
Nat Med ; 24(9): 1313-1316, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30061696

RESUMEN

Intestinal microbial dysbiosis has been described in individuals with an HIV-1 infection and may underlie persistent inflammation in chronic infection, thereby contributing to disease progression. Herein, we induced an HIV-1-like intestinal dysbiosis in rhesus macaques (Macaca mulatta) with vancomycin treatment and assessed the contribution of dysbiosis to SIV disease progression. Dysbiotic and control animals had similar disease progression, indicating that intestinal microbial dysbiosis similar to that observed in individuals with HIV is not sufficient to accelerate untreated lentiviral disease progression.


Asunto(s)
Progresión de la Enfermedad , Disbiosis/microbiología , Síndrome de Inmunodeficiencia Adquirida del Simio/microbiología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Macaca mulatta , Masculino , Vancomicina/farmacología
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