Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa.
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ABSTRACT:
SUBMITTER: Redd AD
PROVIDER: S-EPMC2667149 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gender differences in immune response and the rate of disease progression in HIV-infected individuals have been reported but the underlying mechanism remains unclear, in part because of the lack of relevant animal models. Here, we report a novel nonhuman primate model for investigation of sex disparity in HIV disease progression.Viral load and rate of disease progression were evaluated in rhesus macaques infected intrarectally with lineage-related subtype C R5 simian HIVs. Cytokine/chemokine levels in rectal swab eluates, and bacterial species adherent to the swabs and in the feces were determined.Simian HIV-infected female rhesus macaques progressed faster to AIDS than male macaques, recapitulating the sex bias in HIV-1 disease in humans. There were no significant differences in the levels of soluble immune mediators in the rectal mucosa of naive female and male macaques. However, an exploratory longitudinal study in six infected macaques indicates that the female macaques mounted an earlier and more robust proinflammatory skewed rectal immune response to infection. Moreover, expansion of Proteobacteria that increase in other intestinal inflammatory disorders was significantly higher in the rectal mucosa of female than male macaques during acute infection.These findings suggest that sex differences in local innate immune activation and compositional shifts in the gut microbiota could be the drivers of increased disease susceptibility in female macaques. Further studies with this novel nonhuman primate model of HIV infection could lead to innovative research on gender differences, which may have important therapeutic implications for controlling disease in infected men as well as women.
| S-EPMC4542014 | biostudies-literature
Project description:Both T-cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown.To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression.Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection.The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set point 12 months postinfection and time taken for CD4 cell counts to fall below 350 cells/microl were determined using multivariate and Cox proportional hazards regression.We found that the concentrations of five plasma cytokines, IL-12p40, IL-12p70, IFN-gamma, IL-7 and IL-15 in women with acute infection predicted 66% of the variation in viral load set point 12 months postinfection. IL-12p40, IL-12p70 and IFN-gamma were significantly associated with lower viral load, whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and granulocyte-macrophage colony-stimulating factor during acute infection were associated with maintenance of CD4 cell counts above 350 cells/microl, whereas IL-1alpha, eotaxin and IL-7 were associated with more rapid CD4 loss.A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women.
| S-EPMC3001189 | biostudies-literature
Project description:BackgroundThe relationships between soluble CD14 (sCD14), endotoxin (lipopolysaccharide [LPS]), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) infection.MethodsWe retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group [ACTG] 5078), where subjects were enrolled as risk factor-controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)-based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (ΔCIMT).ResultsIn multivariate analysis of the HIV-infected subjects, each 1 µg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 µm/y (95% confidence interval, .07-2.98; P = .04) in the ΔCIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 µm/y (95% confidence interval, .18-.81; P = .003) in the ΔCIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ΔCIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1).ConclusionsOur data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.
| S-EPMC3475633 | biostudies-literature
Project description:We examined the association between a history of smallpox vaccination and immune activation (IA) in a population of antiretroviral therapy-naïve people living with HIV (PLHIV). A cross-sectional study was conducted in Senegal from July 2015 to March 2017. Smallpox vaccination was ascertained by the presence of smallpox vaccine scar and IA by the plasma level of β-2-microglobulin (β2m). The association was analysed using logistic regression and linear regression models. The study population comprised 101 PLHIV born before 1980 with a median age of 47 years (interquartile range (IQR) = 42-55); 57·4% were women. Smallpox vaccine scar was present in 65·3% and the median β2m level was 2·59 mg/l (IQR = 2·06-3·86). After adjustment, the presence of smallpox vaccine scar was not associated with a β2m level ⩾2·59 mg/l (adjusted odds ratio 0·94; 95% confidence interval 0·32-2·77). This result was confirmed by the linear regression model. Our study does not find any association between the presence of smallpox vaccine scar and the β2m level and does not support any association between a previous smallpox vaccination and HIV disease progression. In this study, IA is not a significant determinant of the reported non-targeted effect of smallpox vaccination in PLHIV.
| S-EPMC5791884 | biostudies-literature
Project description:IntroductionLong-term natural history cohorts of HIV-1 in the absence of treatment provide the best measure of virulence by different viral subtypes.MethodsNewly HIV infected Ugandan and Zimbabwean women (N=303) were recruited and monitored for clinical, social, behavioral, immunological and viral parameters for 3 to 9.5years.ResultsUgandan and Zimbabwean women infected with HIV-1 subtype C had 2.5-fold slower rates of CD4 T-cell declines and higher frequencies of long-term non-progression than those infected with subtype A or D (GEE model, P<0.001), a difference not associated with any other clinical parameters. Relative replicative fitness and entry efficiency of HIV-1 variants directly correlated with virulence in the patients, subtype D>A>C (P<0.001, ANOVA).DiscussionHIV-1 subtype C was less virulent than either A or D in humans; the latter being the most virulent. Longer periods of asymptomatic HIV-1 subtype C could explain the continued expansion and dominance of subtype C in the global epidemic.
| S-EPMC5264310 | biostudies-literature
Project description: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.
| S-EPMC5853564 | biostudies-literature
Project description:Sub-Saharan Africans infected with HIV-1C make up the largest AIDS patient population in the world and exhibit large heterogeneity in disease progression before initiating antiretroviral therapy. To identify host variants associated with HIV disease progression, we performed genome-wide association studies on a total of 556 treatment-naive HIV-infected individuals in Botswana. We characterized the pattern of HIV disease progression using a novel functional principal component analysis, which can better capture longitudinal CD4 and viral load (VL) trajectories. Two single-nucleotide polymorphisms (SNPs) near HCG22 (chr6, peak variant rs2535307, combined p?=?3.72?×?10-7, minor allele as risky allele) and CCNG1 (chr5, peak variant kgp22385164, combined p?=?1.88?×?10-6, minor allele as risky allele) were significantly associated with CD4 and VL dynamics. Inspection of SNPs in these gene regions in a third Botswana cohort (using GWATCH) also revealed a strong association of HCG22 with HIV-1C acquisition, suggesting that this region is associated with infection as well as disease progression. Our study uncovered two genetic regions that are significant and have specific effects on HIV-1C acquisition or progression in sub-Saharan Africans, and the result suggested new potential targets for AIDS prevention and treatment. In addition, our results also indicate the possibility of using genetic markers as HIV disease progression indicators in sub-Saharan Africans to prioritize fast progressors for antiretroviral treatment.
| S-EPMC5467143 | biostudies-literature
Project description:Microbial translocation (MT) is characterized by bacterial products passing into the blood through the gut barrier and is a key phenomenon in the pathophysiology of Human Immunodeficiency Virus (HIV) infection. MT is also associated with liver damage in Hepatitis C Virus (HCV) patients. The aim of the study was to assess MT in plasma of HIV-HCV co-infected patients. 16S rDNA (16 S Ribosomal DNA subunit) marker and other markers of MT such as Lipopolysaccharide (LPS)-binding protein (LBP), soluble CD14 (sCD14), intestinal fatty acid binding protein (I-FABP) were used. Clinical, biological and immunological characteristics of the population were studied in order to correlate them with the intensity of the MT. We demonstrate that indirect markers of MT, LBP and CD14s, and a marker of intestinal permeability (I-FABP) are significantly higher in HIV-HCV co-infected patients than in healthy controls (17.0 vs 2.6 ?g/mL, p < 0.001; 1901.7 vs 1255.0 ng/mL, p = 0.018); 478.3 vs 248.1 pg/mL, p < 0.001, respectively), while a direct marker of MT (16S rDNA copies) is not different between these two populations. However, plasma 16S rDNA was significantly higher in co-infected patients with long-standing HIV infections (RGM = 1.47 per 10 years, CI95% = [1.04:2.06], p = 0.03). Our findings show that in HIV-HCV co-infected patients, plasma 16S rDNA levels, directly reflecting MT, seem to be linked to the duration of HIV infection, while elevated levels of LBP and sCD14 reflect only a persistence of immune activation. The levels of these markers were not correlated with HCV evolution.
| S-EPMC5608492 | biostudies-literature
Project description:Infections with mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis (M. bovis) BCG, are a leading cause of morbidity and mortality for HIV-infected persons. In contrast to HIV, nonpathogenic SIV infections of sooty mangabeys are characterized by a lack of clinical disease including an absence of opportunistic infections. The goal of this study was to identify innate immune responses to M. bovis BCG maintained during nonpathogenic lentiviral infections through a comparison of functional responses during pathogenic HIV or nonpathogenic SIV infections. Monocytes were evaluated for their ability to express key anti-mycobacterial cytokines TNF-α and IL-12 following a six-hour ex vivo BCG exposure. While HIV-infection was associated with a decreased percentage of IL-12-producing monocytes, nonpathogenic SIV-infection was associated with an increased percentage of monocytes producing both cytokines. Gene expression analysis of PBMC following ex vivo BCG exposure identified differential expression of NK cell-related genes and several cytokines, including IFN-γ and IL-23, between HIV-infected and control subjects. In contrast, SIV-infected and uninfected-control mangabeys exhibited no significant differences in gene expression after BCG exposure. Finally, differential gene expression patterns were identified between species, with mangabeys exhibiting lower IL-6 and higher IL-17 in response to BCG when compared to humans. Overall, this comparison of immune responses to M. bovis BCG identified unique immune signatures (involving cytokines IL-12, TNF-α, IL-23, IL-17, and IL-6) that are altered during HIV, but maintained or increased during nonpathogenic SIV infections. These unique cytokine and transcriptome signatures provide insight into the differential immune responses to Mycobacteria during pathogenic HIV-infection that may be associated with an increased incidence of mycobacterial co-infections.
| S-EPMC4978473 | biostudies-literature
Project description:BACKGROUND:Co-infection with HIV negatively impacts the progression of chronic hepatitis B virus (HBV) infection, including causing rapid progression to liver fibrosis. Sub-Saharan Africa represents arguably the most important intersection of high endemicity of both chronic hepatitis B virus (HBV) infection and HIV infection. METHODS:We recruited 46 HBV/HIV-co-infected; 47 HBV-monoinfected; 39 HIV-monoinfected; and 37 HBV/HIV-uninfected patients from Tygerberg Hospital, Cape Town, South Africa. All HIV-infected patients were on antiretroviral therapy for ?3 months. Liver stiffness measurements were assessed using the Fibroscan (Fibroscan 402, Echosens). Cell-based immunomarkers were measured by flow cytometry. Soluble serum/plasma immunomarkers were measured by Luminex technology and enzyme immunoassays. HIV (COBAS/Ampliprep TaqMan HIV-1) and HBV viral loads (in-house assay) were also performed. RESULTS:HBV/HIV co-infected patients showed significantly higher levels of immune activation %CD8+/HLA-DR+/CD38+ (median 30%, interquartile range: 17-53) and %CD8+/PD-1 (median 22%, interquartile range: 15-33), p???0.01 compared to all other study groups. Despite this, the HBV-mono-infected group had the highest proportion of patients with advanced liver fibrosis (?13 kPa) as measured by Fibroscan (18%). HBV mono-infected patients showed highest expression of most cytokines including IL-17 and basic fibroblastic growth factor. There was significant positive correlation between detectable HIV and HBV viral replication and liver fibrosis but not immune activation or gut translocation. DISCUSSION:Highly-active antiretroviral therapy, including tenofovir, is effective against both HIV and HBV. Earlier therapy in the co-infected patients may therefore have controlled viral replication leading to better fibrosis scores when compared to HBV mono-infection in this study. On-going HBV and HIV viraemia, rather than microbial translocation or immune activation, appear to be the drivers of liver fibrosis. Moderate to advanced liver fibrosis in HBV-mono-infection may well indicate poor access to screening and treatment of HBV infection.
| S-EPMC5941637 | biostudies-literature