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Review on the Alteration of Gut Microbiota: The Role of HIV Infection and Old Age.
Ashuro, AA, Lobie, TA, Ye, DQ, Leng, RX, Li, BZ, Pan, HF, Fan, YG
AIDS research and human retroviruses. 2020;(7):556-565
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Abstract
Human immunodeficiency virus (HIV) infection results in gut microbiota alteration and this is associated with immune activation and chronic inflammation. The gastrointestinal tract is a primary site of viral replication and thus HIV-induced loss of T-helper (Th) cells in the gut causes impairments in intestinal barriers, resulting in disruptions in intestinal immunity and precipitating into gut dysbiosis. Here, we show that late HIV diagnosis can negatively affect the immunological, virological, and clinical prognosis of the patients with its higher implication at an older age. Further, the review indicates that antiretroviral therapy affects the gut microbiota. We discussed the use of probiotics and prebiotics that have been indicated to play a promising role in reversing gut microbiota alteration in HIV patients. Though there are several studies reported with regard to such alterations in gut microbiota regarding HIV infection, there is a need to provide comprehensive updates. It is, therefore, the objective of this review to present most recently available evidence on the alteration of gut microbiota among HIV patients.
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Monocyte and T Cell Immune Phenotypic Profiles Associated With Age Advancement Differ Between People With HIV, Lifestyle-Comparable Controls and Blood Donors.
De Francesco, D, Sabin, CA, Reiss, P, Kootstra, NA
Frontiers in immunology. 2020;:581616
Abstract
MOTIVATION People with HIV on successful antiretroviral therapy show signs of premature aging and are reported to have higher rates of age-associated comorbidities. HIV-associated immune dysfunction and inflammation have been suggested to contribute to this age advancement and increased risk of comorbidities. METHOD Partial least squares regression (PLSR) was used to explore associations between biological age advancement and immunological changes in the T cell and monocyte compartment in people with HIV (n=40), comparable HIV-negative individuals (n=40) participating in the Comorbidity in Relation to AIDS (COBRA) cohort, and blood donors (n=35). RESULTS We observed that age advancement in all three groups combined was associated with a monocyte immune phenotypic profile related to inflammation and a T cell immune phenotypic associated with immune senescence and chronic antigen exposure. Interestingly, a unique monocyte and T cell immune phenotypic profile predictive for age advancement was found within each group. An inflammatory monocyte immune phenotypic profile associated with age advancement in HIV-negative individuals, while the monocyte profile in blood donors and people with HIV was more reflective of loss of function. The T cell immune phenotypic profile in blood donors was related to loss of T cell function, whereas the same set of markers were related to chronic antigen stimulation and immune senescence in HIV-negative individuals. In people with HIV, age advancement was related to changes in the CD4+ T cell compartment and more reflective of immune recovery after cART treatment. IMPACT The identified monocyte and T cell immune phenotypic profiles that were associated with age advancement, were strongly related to inflammation, chronic antigen exposure and immune senescence. While the monocyte and T cell immune phenotypic profile within the HIV-negative individuals reflected those observed in the combined three groups, a distinct profile related to immune dysfunction, was observed within blood donors and people with HIV. These data suggest that varying exposures to lifestyle and infection-related factors may be associated with specific changes in the innate and adaptive immune system, that all contribute to age advancement.
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Zim CHIC: A cohort study of immune changes in the female genital tract associated with initiation and use of contraceptives.
Achilles, SL, Meyn, LA, Mhlanga, FG, Matubu, AT, Stoner, KA, Beamer, MA, Chirenje, ZM, Hillier, SL
American journal of reproductive immunology (New York, N.Y. : 1989). 2020;(3):e13287
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Abstract
PROBLEM Contraceptive hormones are systemically active, potent, and likely to invoke biological responses other than known fertility regulation impacts. We hypothesized that initiation of depot medroxyprogesterone acetate (DMPA) would increase genital HIV-target-cells and soluble immune mediators compared with baseline and initiation of other contraceptive methods. METHOD OF STUDY We collected cervical cytobrushes and cervicovaginal fluid from healthy Zimbabwean women aged 18-34 to assess immune cell populations, cytokines, and innate anti-HIV activity at baseline and after 30, 90, and 180 days use of DMPA (n = 38), norethisterone enanthate (n = 41), medroxyprogesterone acetate/estradiol cypionate (n = 36), levonorgestrel implant (n = 43), etonogestrel implant (n = 47), or copper intrauterine device (Cu-IUD) (n = 45). Cells were quantified by flow cytometry, cytokines were detected by multiplex assays, and innate anti-HIV activity was assessed by in vitro HIV challenge. RESULTS Compared to baseline, the number of cervical HIV target cells (#CD4 cells P < .04 and #CD11c cells P < .04), the concentration of the inflammatory cytokine IL-1β (P < .01), and the innate in vitro anti-HIV activity (P < .001) significantly decreased following DMPA initiation. In Cu-IUD users, genital HIV target cells increased (#CD4 cells P < .001, #CD4CCR5 cells P = .02, #CD4CD69 cells P < .001, #CD8CD69 P = .01, and #CD11c cells P = .003) at day 30 and resolved by day 180. IFN-γ (P < .001), IL-1β (P < .001), IL-6 (P < .001), IL-8 (P < .001), IL-10 (P < .01), and RANTES (P < .001) were also significantly increased at day 30. Minimal alterations were observed following initiation of subdermal implantable contraceptives. CONCLUSIONS This head-to-head study compared six contraceptives and found increased HIV target cells and cervical inflammation temporally associated with Cu-IUD initiation. Use of hormonal contraception, including DMPA, did not increase cervical HIV target cells or inflammation. Clinical Trial Number: NCT02038335.
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Magnitude of underweight, wasting and stunting among HIV positive children in East Africa: A systematic review and meta-analysis.
Abate, BB, Aragie, TG, Tesfaw, G
PloS one. 2020;(9):e0238403
Abstract
BACKGROUND Malnutrition on the background of HIV (Human Immunodeficiency Virus) infection is a complex medical condition that carries significant morbidity and mortality for affected children, with greater mortality from SAM (Severe Acute Malnutrition) among HIV-positive children than their HIV-negative peers. HIV-induced immune impairment heightened risk of opportunistic infection and can worsen nutritional status of children. HIV infection often leads to nutritional deficiencies through decreased food intake, mal-absorption and increased utilization and excretion of nutrients, which in turn can hasten death. OBJECTIVE The aim of this systematic review and meta-analysis was to assess the magnitude of underweight, wasting and stunting among HIV positive children in East Africa. METHODS The authors systematically reviewed and meta-analyzed studies that assessed the prevalence of underweight, wasting and stunting among HIV positive children in East Africa from PubMed, Cochrane Library, Google Scholar, and Gray Literatures using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. The last search date was December 30/2019. The data was extracted in excel sheet considering country, study design, year of publication, prevalence reported. Then the authors transformed the data to STATA 14 for analysis. Heterogeneity across the studies was assessed by the Q and the I2 test. A weighted inverse variance random-effects model was used to estimate the magnitude of underweight, wasting and stunting. The subgroup analysis was done by country, year of publication, and study design. To examine publication bias, a funnel plot and Egger's regression test were used. RESULTS For the analysis a total of 22 studies with 22074 patients were used. The pooled prevalence of under-weight, wasting, and stunting among HIV positive children in East Africa was found to be 41.63% (95%CI; 35.69-47.57; I2 = 98.7%; p<0.001), 24.65% (95%CI; 18.34-30.95; I2 = 99.2%; p<0.001), and 49.68% (95%CI; 42.59-56.77; I2 = 99.0%; p<0.001) respectively. The prevalence of under-weight among HIV positive children was found to be 49.67% in Ethiopia followed by 42.00 in Rwanda. It was high among cohort studies (44.87%). Based on the year of publication, the prevalence of under-weight among HIV positive children was found to be 40.88% from studies conducted from January 2008-December 2014, while it was 43.68% from studies conducted from 2015-2019. The prevalence of wasting among HIV positive children was found to be 29.7% in Tanzania followed by 24.94% in Ethiopia. Based on the study design, the prevalence of wasting among HIV positive children was found to be high in cohort studies (31.15%). The prevalence of stunting among HIV positive children was found to be 51.63% in Ethiopia, followed by 48.21% in Uganda. CONCLUSIONS The results presented above provide evidence of a higher prevalence of under nutrition among HIV positive children in East Africa. Despite the country level variations of child under nutrition in East Africa, still it is high in all aspects compared to the studies from other parts of Africa. It is recommended that further systematic review and meta-analysis need to be conducted on magnitude of malnutrition among HIV positive children in Sub-Saharan Africa as a whole.
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Early Progression and Immune Reconstitution Inflammatory Syndrome During Treatment of Mild-To-Moderate Kaposi Sarcoma in Sub-Saharan Africa and South America: Incidence, Long-Term Outcomes, and Effects of Early Chemotherapy.
Nyirenda, M, Ngongondo, M, Kang, M, Umbleja, T, Krown, SE, Godfrey, C, Samaneka, W, Mngqibisa, R, Hoagland, B, Mwelase, N, et al
Journal of acquired immune deficiency syndromes (1999). 2020;(4):422-429
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BACKGROUND Early progression of AIDS-associated Kaposi sarcoma (KS-PD) and immune reconstitution inflammatory syndrome (KS-IRIS) sometimes occur after the initiation of antiretroviral therapy (ART). METHODS Early KS-PD and KS-IRIS were assessed in the A5264/AMC-067 trial in which participants with mild-to-moderate AIDS-KS were randomized to initiate ART with either immediate or as-needed oral etoposide. Early KS-PD was defined as tumor progression within 12 weeks of ART initiation. When investigators had concern that early KS-PD was KS-IRIS, additional evaluations were performed. Suspected KS-IRIS was defined as early KS-PD accompanied by a CD4 count increase of ≥50 cells per cubic millimeter or plasma HIV-1 RNA decrease of ≥0.5 log10 copies/mL. Clinical outcome was a composite end point categorized as failure, stable, and response at 48 and 96 weeks compared with baseline. RESULTS Fifty of 190 participants had early KS-PD (27%): 28 had KS-IRIS and 22 were not evaluated for KS-IRIS. Early KS-PD and KS-IRIS incidences with immediate etoposide versus ART alone were 16% versus 39%, and 7% versus 21%, respectively. Week 48 clinical outcome was 45% failure, 18% stable, and 37% response for no early KS-PD; 82% failure, 2% stable, and 16% response for early KS-PD; and 88% failure, 0% stable, and 12% response for KS-IRIS. Cumulative incidence of KS tumor response by week 96 was 64% for no early KS-PD, 22% with early KS-PD, and 18% with KS-IRIS. CONCLUSIONS Early KS-PD, including suspected KS-IRIS, was common after starting ART for AIDS-KS and was associated with worse long-term clinical outcomes. Starting ART concurrently with etoposide reduced the incidence of both early KS-PD and KS-IRIS compared with ART alone.
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Brief Report: Dipyridamole Decreases Gut Mucosal Regulatory T-Cell Frequencies Among People With HIV on Antiretroviral Therapy.
Mallarino-Haeger, C, Abebe, KZ, Jackson, EK, Zyhowski, A, Klamar-Blain, C, Cyktor, JC, Comer, D, Brand, RM, Gillespie, DG, Holleran, K, et al
Journal of acquired immune deficiency syndromes (1999). 2020;(5):665-669
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Abstract
BACKGROUND We had previously conducted a double-blind, randomized placebo-controlled, partial cross-over trial showing that 12 weeks of dipyridamole decreased CD8 T-cell activation among treated HIV(+) individuals by increasing extracellular adenosine levels. METHODS In this substudy, rectosigmoid biopsies were obtained from 18 participants (9 per arm), to determine whether 12 weeks of dipyridamole affects mucosal immune cells. Participants randomized to placebo were then switched to dipyridamole for 12 weeks while the treatment arm continued dipyridamole for another 12 weeks. We evaluated T-cell frequencies and plasma markers of microbial translocation and intestinal epithelial integrity. Linear regression models on log-transformed outcomes were used for the primary 12-week analysis. RESULTS Participants receiving dipyridamole had a median 70.2% decrease from baseline in regulatory T cells (P = 0.007) and an 11.3% increase in CD8 T cells (P = 0.05). There was a nonsignificant 10.80% decrease in plasma intestinal fatty acid binding protein levels in the dipyridamole arm compared with a 9.51% increase in the placebo arm. There were no significant differences in plasma levels of β-D-glucan. In pooled analyses, there continued to be a significant decrease in regulatory T cells (-44%; P = 0.004). There was also a trend for decreased CD4 and CD8 T-cell activation. CONCLUSION Increasing extracellular adenosine levels using dipyridamole in virally suppressed HIV (+) individuals on antiretroviral therapy can affect regulation of gut mucosal immunity.
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Statin Therapy Does Not Reduce Liver Fat Scores in Patients Receiving Antiretroviral Therapy for HIV Infection.
El Kamari, V, Hileman, CO, Gholam, PM, Kulkarni, M, Funderburg, N, McComsey, GA
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(3):536-542.e1
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BACKGROUND & AIMS Therapies are needed to limit progression of fatty liver diseases in patients with human immunodeficiency virus (HIV) infection. We analyzed data from a prospective study of the effects of rosuvastatin (a statin) on hepatic steatosis in HIV-positive adults. METHODS We performed a secondary analysis of data from a double-blind trial of adult patients with HIV infection (78% male; 68% African American; mean age, 46 y; body mass index, 29 kg/m2; HIV1 RNA < 1000 copies/mL; low-density lipoprotein cholesterol, <130 mg/dL) receiving antiretroviral therapy. The patients were randomly assigned to groups given 10 mg daily rosuvastatin (n = 72) or placebo (n = 75). Demographic and clinical data were collected, and blood samples were analyzed. Changes in liver fat score (LFS, a composite score calculated from metabolic and liver function parameters) and markers of systemic inflammation and immune activation were assessed through 96 weeks of drug or placebo administration. We performed multivariable linear and logistic regressions to study relationships among variables. RESULTS The placebo and rosuvastatin groups each had significant increases in LFS, compared with baseline, at 96 weeks (P = .01 and P < .01; P = .49 for difference increase between groups). Baseline LFS was independently associated with blood level of C-X-C motif chemokine ligand 10 (P = .04) and the soluble CD163 molecule (P = .01). After we adjusted for baseline characteristics, an increase in LFS over time was significantly associated with the blood level of C-X-C motif chemokine ligand 10 (P = .04), insulin resistance (P < .01), and viral load (P = .02), but not rosuvastatin use (P = .06). CONCLUSIONS In a secondary analysis of data from a trial of patients receiving treatment for HIV infection, hepatic steatosis increased over time, regardless of statin treatment, and was independently associated with markers of immune activation. Patients who received rosuvastatin appeared to have a nonsignificant increase in hepatic steatosis over 96 weeks. Despite their ability to reduce the risk of cardiovascular disease, statins do not appear to reduce hepatic steatosis. Clinicaltrials.gov no: NCT01218802.
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The Potential Protective Role of Vitamin D Supplementation on HIV-1 Infection.
Alvarez, N, Aguilar-Jimenez, W, Rugeles, MT
Frontiers in immunology. 2019;:2291
Abstract
HIV infection remains a global and public health issue with the incidence increasing in some countries. Despite the fact that combination antiretroviral therapy (cART) has decreased mortality and increased the life expectancy of HIV-infected individuals, non-AIDS conditions, mainly those associated with a persistent inflammatory state, have emerged as important causes of morbidity, and mortality despite effective antiviral therapy. One of the most common comorbidities in HIV-1 patients is Vitamin D (VitD) insufficiency, as VitD is a hormone that, in addition to its physiological role in mineral metabolism, has pleiotropic effects on immune regulation. Several reports have shown that VitD levels decrease during HIV disease progression and correlate with decreased survival rates, highlighting the importance of VitD supplementation during infection. An extensive review of 29 clinical studies of VitD supplementation in HIV-infected patients showed that regardless of cART, when VitD levels were increased to normal ranges, there was a decrease in inflammation, markers associated with bone turnover, and the risk of secondary hyperparathyroidism while the anti-bacterial response was increased. Additionally, in 3 of 7 studies, VitD supplementation led to an increase in CD4+ T cell count, although its effect on viral load was inconclusive since most patients were on cART. Similarly, previous evidence from our laboratory has shown that VitD can reduce the infection of CD4+ T cells in vitro. The effect of VitD supplementation on other HIV-associated conditions, such as cardiovascular diseases, dyslipidemia or hypertension, warrants further exploration. Currently, the available evidence suggests that there is a potential role for VitD supplementation in people living with HIV-1, however, comprehensive studies are required to define an adequate supplementation protocol for these individuals.
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Influence of AIDS antiretroviral therapy on the growth pattern.
Golucci, APBS, Marson, FAL, Valente, MFF, Branco, MM, Prado, CC, Nogueira, RJN
Jornal de pediatria. 2019;(1):7-17
Abstract
OBJECTIVES Human immunodeficiency virus infection can result in the early impairment of anthropometric indicators in children and adolescents. However, combined antiretroviral therapy has improved, in addition to the immune response and viral infection, the weight and height development in infected individuals. Therefore, the objective was to evaluate the effect of combined antiretroviral on the growth development of human immunodeficiency virus infected children and adolescents. SOURCE OF DATA A systematic review was performed. In the study, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) strategy was used as the eligibility criterion. The MEDLINE-PubMed and LILACS databases were searched using these descriptors: HIV, children, growth, antiretroviral therapy. The objective was defined by the population, intervention, comparison/control, and outcome (PICO) technique. Inclusion and exclusion criteria were applied for study selection. SYNTHESIS OF DATA Of the 549 studies indexed in MEDLINE-PubMed and LILACS, 73 were read in full, and 44 were included in the review (33 showed a positive impact of combined antiretroviral therapy on weight/height development, ten on weight gain, and one on height gain in children and adolescents infected with human immunodeficiency virus). However, the increase in growth was not enough to normalize the height of infected children when compared to children of the same age and gender without human immunodeficiency virus infection. CONCLUSIONS Combined antiretroviral therapy, which is known to play a role in the improvement of viral and immunological markers, may influence in the weight and height development in children infected with human immunodeficiency virus. The earlier the infection diagnosis and, concomitantly, of malnutrition and the start of combined antiretroviral therapy, the lower the growth impairment when compared to healthy children.
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Vitamin D and Phenylbutyrate Supplementation Does Not Modulate Gut Derived Immune Activation in HIV-1.
Missailidis, C, Sørensen, N, Ashenafi, S, Amogne, W, Kassa, E, Bekele, A, Getachew, M, Gebreselassie, N, Aseffa, A, Aderaye, G, et al
Nutrients. 2019;(7)
Abstract
Dysbiosis and a dysregulated gut immune barrier function contributes to chronic immune activation in HIV-1 infection. We investigated if nutritional supplementation with vitamin D and phenylbutyrate could improve gut-derived inflammation, selected microbial metabolites, and composition of the gut microbiota. Treatment-naïve HIV-1-infected individuals (n = 167) were included from a double-blind, randomized, and placebo-controlled trial of daily 5000 IU vitamin D and 500 mg phenylbutyrate for 16 weeks (Clinicaltrials.gov NCT01702974). Baseline and per-protocol plasma samples at week 16 were analysed for soluble CD14, the antimicrobial peptide LL-37, kynurenine/tryptophan-ratio, TMAO, choline, and betaine. Assessment of the gut microbiota involved 16S rRNA gene sequencing of colonic biopsies. Vitamin D + phenylbutyrate treatment significantly increased 25-hydroxyvitamin D levels (p < 0.001) but had no effects on sCD14, the kynurenine/tryptophan-ratio, TMAO, or choline levels. Subgroup-analyses of vitamin D insufficient subjects demonstrated a significant increase of LL-37 in the treatment group (p = 0.02), whereas treatment failed to significantly impact LL-37-levels in multiple regression analysis. Further, no effects on the microbiota was found in number of operational taxonomic units (p = 0.71), Shannon microbial diversity index (p = 0.82), or in principal component analyses (p = 0.83). Nutritional supplementation with vitamin D + phenylbutyrate did not modulate gut-derived inflammatory markers or microbial composition in treatment-naïve HIV-1 individuals with active viral replication.