Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques.
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ABSTRACT:
SUBMITTER: Boby N
PROVIDER: S-EPMC8066988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epithelial cell injury and impaired epithelial regeneration are considered key features in HIV pathogenesis and contribute to HIV-induced generalized immune activation. Understanding the molecular mechanisms underlying the disrupted epithelial regeneration might provide an alternative approach for the treatment of HIV-mediated enteropathy and immune activation. We have observed a significant increased presence of α defensin5+ (HD5) Paneth cells and proliferating Ki67+ epithelial cells as well as decreased expression of E-cadherin expression in epithelial cells during SIV infection. SIV infection did not significantly influence the frequency of LGR5+ stem cells, but the frequency of HD5+ cells was significantly higher compared to uninfected controls in jejunum. Our global transcriptomics analysis of enteroids provided novel information about highly significant changes in several important pathways like metabolic, TCA cycle, and oxidative phosphorylation, where the majority of the differentially expressed genes were downregulated in enteroids grown from chronically SIV-infected macaques compared to the SIV-uninfected controls. Despite the lack of significant reduction in LGR5+ stem cell population, the dysregulation of several intestinal stem cell niche factors including Notch, mTOR, AMPK and Wnt pathways as well as persistence of inflammatory cytokines and chemokines and loss of epithelial barrier function in enteroids further supports that SIV infection impacts on epithelial cell proliferation and intestinal homeostasis.
| S-EPMC8650114 | biostudies-literature
Project description:Activated CD8+ T-cells correlate with viral load and may foretell antiretroviral therapy (ART) failure. HIV infection has been suggested to accelerate immunosenescence through chronic persistent inflammation. Alcohol-use disorders (AUD) are prevalent in persons living with HIV/AIDS (PLWHA). We tested the hypothesis that hazardous alcohol consumption accelerates immune activation and immunosenescence. Immune activation and immunosenescence were examined in CD8+ T lymphocytes (CD3+CD4-CD8+) isolated from intestinal biopsies, axillary lymph nodes, and peripheral blood mononuclear cells (PBMCs) of chronic binge alcohol (CBA)-consuming simian immunodeficiency virus (SIV)-infected male rhesus macaques with and without antiretroviral therapy (ART; CBA/ART+, CBA/ART-) and in PBMCs isolated from a cohort of PLWHA. Polychromatic flow cytometry was used to phenotype cells isolated from intestinal biopsies, lymph nodes, and peripheral blood from rhesus macaques and PLWHA. The Alcohol Use Disorders Identification Test (AUDIT) identified hazardous alcohol drinking in PLWHA. Viral load was determined by RT-qPCR and telomere length was measured using qPCR. PBMC CD8+ T-cell activation (CD38+HLA-DR+) and immunosenescence (CD28-) were increased over baseline levels (857% ± 334, p < 0.05; 398% ± 80, p < 0.05, respectively) only in CBA animals not receiving ART. Viral load correlated with CD8+ T-cell immunosenescence in macaque PBMCs (r(s) = 0.49, p = 0.02). Activated immunosenescent T-cell (CD8+CD38+CD28-) frequencies in PBMCs from PLWHA significantly correlated with AUDIT scores (r(s) = 0.75, p = 0.001), while no correlation was observed with CD4+ T-cell and AUDIT scores (r(s) = -0.24, p = 0.38). Activated immunosenescent T-cells had shorter telomeres than CD8+ T-cells (CD8+CD28+) from PLWHA. Our results suggest that CBA and AUD augment immune activation and immunosenescence in SIV-infected macaques and PLWHA.
| S-EPMC4691397 | biostudies-literature
Project description:Toll-like receptors (TLRs) are crucial to the innate immune response. They regulate inflammatory reactions by initiating the production of pro-inflammatory cytokines and chemokines. TLRs also play a role in shaping the adaptive immune responses. While this protective response is important for eliminating infectious pathogens, persistent activation of TLRs may result in chronic immune activation, leading to detrimental effects. The role of TLR2 in regulating HIV-1 infection in vivo has yet to be well described. In this study, we used an SIV-infected rhesus macaque model to simulate HIV infection in humans. We evaluated the plasma of the macaques longitudinally and found a significant increase in the soluble TLR2 (sTLR2) level after SIV infection. We also observed an increase in membrane-bound TLR2 (mb-TLR2) in cytotoxic T cells, B cells, and NK cells in PBMC and NK cells in the gut after infection. Our results suggest that sTLR2 regulates the production of various cytokines and chemokines, including IL-18, IL-1RA, IL-15, IL-13, IL-9, TPO, FLT3L, and IL-17F, as well as chemokines, including IP-10, MCP-1, MCP-2, ENA-78, GRO-α, I-TAC, Fractalkine, SDF-1α, and MIP-3α. Interestingly, these cytokines and chemokines were also upregulated after the infection. The positive correlation between SIV copy number and sTLR2 in the plasma indicated the involvement of TLR2 in the regulation of viral replication. These cytokines and chemokines could directly or indirectly regulate viral replication through the TLR2 signaling pathways. When we stimulated PBMC with the TLR2 agonist in vitro, we observed a direct induction of various cytokines and chemokines. Some of these cytokines and chemokines, such as IL-1RA, IL-9, IL-15, GRO-α, and ENA-78, were positively correlated with sTLR2 in vivo, highlighting the direct involvement of TLR2 in the regulation of the production of these factors. Our findings suggest that TLR2 expression may be a target for developing new therapeutic strategies to combat HIV infection.
| S-EPMC10747659 | biostudies-literature
Project description:Despite effective antiretroviral therapy, HIV co-morbidities remain where central nervous system (CNS) neurocognitive disorders and cardiovascular disease (CVD)-pathology that are linked with myeloid activation are most prevalent. Comorbidities such as neurocogntive dysfunction and cardiovascular disease (CVD) remain prevalent among people living with HIV. We sought to investigate if cardiac pathology (inflammation, fibrosis, cardiomyocyte damage) and CNS pathology (encephalitis) develop together during simian immunodeficiency virus (SIV) infection and if their co-development is linked with monocyte/macrophage activation. We used a cohort of SIV-infected rhesus macaques with rapid AIDS and demonstrated that SIV encephalitis (SIVE) and CVD pathology occur together more frequently than SIVE or CVD pathology alone. Their co-development correlated more strongly with activated myeloid cells, increased numbers of CD14+CD16+ monocytes, plasma CD163 and interleukin-18 (IL-18) than did SIVE or CVD pathology alone, or no pathology. Animals with both SIVE and CVD pathology had greater numbers of cardiac macrophages and increased collagen and monocyte/macrophage accumulation, which were better correlates of CVD-pathology than SIV-RNA. Animals with SIVE alone had higher levels of activated macrophage biomarkers and cardiac macrophage accumulation than SIVnoE animals. These observations were confirmed in HIV infected individuals with HIV encephalitis (HIVE) that had greater numbers of cardiac macrophages and fibrosis than HIV-infected controls without HIVE. These results underscore the notion that CNS and CVD pathologies frequently occur together in HIV and SIV infection, and demonstrate an unmet need for adjunctive therapies targeting macrophages.
| S-EPMC10641955 | biostudies-literature
Project description:Peripheral neuropathies are common sequelae to human immunodeficiency virus (HIV) infection in humans and are due to a variety of mechanisms, including direct antiretroviral toxicity, HIV-mediated damage, immune-mediated disorders, and opportunistic viral infections. Rhesus macaques (Macaca mulatta) infected with simian immunodeficiency virus (SIV) remain the most consistent animal model for unraveling the pathogenesis of lentiviral-associated disease and its associated opportunistic infections. Rhesus cytomegalovirus (RhCMV) is the most common opportunistic viral infection in rhesus macaques infected with SIV and causes multiorgan pathology; however, its role in peripheral nerve pathology has not been explored. We have identified 115 coinfected cases with SIV and RhCMV, of which 10 cases of RhCMV-associated facial neuritis were found (8.7% prevalence). Histologic lesions were consistent in all cases and ranged from partial to complete obliteration of the nerves of the tongue, lacrimal gland, and other facial tissues with a mixed inflammatory population of neutrophils and macrophages, of which the latter commonly contained intranuclear inclusion bodies. Luxol fast blue staining and myelin basic protein immunohistochemistry confirmed the progressive myelin loss in the peripheral nerves. Bielschowsky silver stain revealed progressive loss of axons directly related to the severity of inflammation. Double immunohistochemistry with spectral imaging analysis revealed RhCMV-infected macrophages directly associated with the neuritis, and there was no evidence to support RhCMV infection of Schwann cells. These results suggest that peripheral nerve damage is a bystander effect secondary to inflammation rather than a direct infection of Schwann cells and warrants further investigations into the pathogenesis of RhCMV-induced peripheral neuropathy.
| S-EPMC4221582 | biostudies-literature
Project description:The intestinal tract is a primary barrier to invading pathogens and contains immune cells, including lymphocytes and macrophages. We previously reported that CD163+CD206- (single-positive [SP]) interstitial macrophages of the lung are short-lived and succumb early to SIV infection. Conversely, CD163+CD206+ (double-positive [DP]) alveolar macrophages are long-lived, survive after SIV infection, and may contribute to the virus reservoir. This report characterizes analogous populations of macrophages in the intestinal tract of rhesus macaques (Macaca mulatta) with SIV/AIDS. By flow cytometry analysis, immunofluorescence staining, and confocal microscopy, CD163+CD206+ DP macrophages predominated in the lamina propria of uninfected animals, compared with CD163+CD206- SP macrophages, which predominated in the lamina propria in animals with SIV infection that were exhibiting AIDS. In submucosal areas, CD163+CD206+ DP macrophages predominated in both SIV-infected and uninfected macaques. Furthermore, BrdU-labeled CD163+CD206+ DP and CD163+CD206- SP macrophages recently arriving in the colon, which are both presumed to be shorter-lived, were observed to localize only in the lamina propria. Conversely, longer-lived CD163+CD206+ DP macrophages that retained dextran at least 2 mo after in vivo administration localized exclusively in the submucosa. This suggests that CD163+CD206+ DP intestinal macrophages of the lamina propria were destroyed after SIV infection and replaced by immature CD163+CD206- SP macrophages, whereas longer-lived CD163+CD206+ DP macrophages remained in the submucosa, supporting their potential role as an SIV/HIV tissue reservoir. Moreover, the DP macrophages in the submucosa, which differ from lamina propria DP macrophages, may be missed from pinch biopsy sampling, which may preclude detecting virus reservoirs for monitoring HIV cure.
| S-EPMC6478513 | biostudies-literature
Project description:HIV-associated pulmonary arterial hypertension (PAH) is likely a more prevalent noninfectious complication of AIDS than previously recognized. Furthermore, the majority of HIV-PAH cases occur in individuals with a history of intravenous drug use. In this study we used a simian immunodeficiency (SIV) macaque model and a primary cell-culture system to investigate the association between drug abuse and HIV infection in HIV-PAH development.The archival lung tissues from macaques previously used to study the effect of morphine on SIV infection-associated neuropathogenesis were analyzed for pulmonary vascular changes. The direct effect of HIV proteins and illicit drugs was investigated on oxidative stress, survival, and proliferation of human pulmonary microvascular endothelial cells.SIVmacR71/17E-infected rhesus macaques treated with morphine (VM group) demonstrated significant pulmonary vascular remodeling, including the presence of early and advanced complex (plexiform) lesions, when compared with either the SIV-infected (V group) or morphine-treated uninfected (M group) macaques. However, both the V (two of five) and VM (two of six) groups included some animals with Pneumocystis jirovecii pneumonia. The endothelial cells lining the vessels with medial hypertrophy or initial-stage intimal lesions in lung sections from VM macaques demonstrated an increase in positivity for both terminal dUTP nick-end labeling and Ki67. Oxidative stress-mediated enhanced apoptosis followed by enhanced proliferation of endothelial cells was observed on simultaneous treatment with viral proteins and drugs of abuse compared with either treatment alone.Our findings suggest that SIV/HIV protein(s) and morphine interact to cause the proliferation of apoptosis-resistant endothelial cells leading to angio-obliteration.
| S-EPMC3373069 | biostudies-literature
Project description:BackgroundCommonly used opioids, such as morphine have been implicated in augmented SIV/HIV persistence within the central nervous system (CNS). However, the extent of myeloid cell polarization and viral persistence in different brain regions remains unclear. Additionally, the additive effects of morphine on SIV/HIV dysregulation of gut-brain crosstalk remain underexplored. Therefore, studies focused on understanding how drugs of abuse such as morphine affect immune dynamics, viral persistence and gut-brain interrelationships are warranted.Materials and methodsFor a total of 9 weeks, rhesus macaques were ramped-up, and twice daily injections of either morphine (n = 4) or saline (n = 4) administered. This was later followed with infection with SHIVAD8EO variants. At necropsy, mononuclear cells were isolated from diverse brain [frontal lobe, cerebellum, medulla, putamen, hippocampus (HIP) and subventricular zone (SVZ)] and gut [lamina propria (LP) and muscularis (MUSC) of ascending colon, duodenum, and ileum] regions. Multiparametric flow cytometry was used to were profile for myeloid cell polarity/activation and results corroborated with indirect immunofluorescence assays. Simian human immunodeficiency virus (SHIV) DNA levels were measured with aid of the digital droplet polymerase chain reaction (PCR) assay. Luminex assays were then used to evaluate soluble plasma/CSF biomarker levels. Finally, changes in the fecal microbiome were evaluated using 16S rRNA on the Illumina NovaSeq platform.ResultsFlow Cytometry-based semi-supervised analysis revealed that morphine exposure led to exacerbated M1 (CD14/CD16)/M2 (CD163/CD206) polarization in activated microglia that spanned across diverse brain regions. This was accompanied by elevated SHIV DNA within the sites of neurogenesis-HIP and SVZ. HIP/SVZ CD16+ activated microglia positively correlated with SHIV DNA levels in the brain (r = 0.548, p = 0.042). Simultaneously, morphine dependence depleted butyrate-producing bacteria, including Ruminococcus (p = 0.05), Lachnospira (p = 0.068) genera and Roseburia_sp_831b (p = 0.068). Finally, morphine also altered the regulation of CNS inflammation by reducing the levels of IL1 Receptor antagonist (IL1Ra).ConclusionThese findings are suggestive that morphine promotes CNS inflammation by altering receptor modulation, increasing myeloid brain activation, distorting gut-brain crosstalk, and causing selective enhancement of SHIV persistence in sites of neurogenesis.
| S-EPMC9613112 | biostudies-literature
Project description:UnlabelledTripartite motif-containing protein 5α (TRIM5α) is considered to be a potential target for cell-based gene modification therapy against human immunodeficiency virus type 1 (HIV-1) infection. In the present study, we used a relevant rhesus macaque model of infection with simian immunodeficiency virus from sooty mangabey (SIVsm) to evaluate the effect of TRIM5α restriction on clinical outcome. For macaques expressing a restrictive TRIM5 genotype, the disease outcomes of those infected with the wild-type TRIM-sensitive SIVsm strain and those infected with a virus with escape mutations in the capsid were compared. We found that TRIM5α restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, supporting the feasibility of exploiting TRIM5α as a target for gene therapy against HIV-1. Furthermore, we also found that preservation of memory CD4 T cells was associated with protection by TRIM5α restriction, suggesting memory CD4 T cells or their progenitor cells as an ideal target for gene modification. Despite the significant effect of TRIM5α restriction on survival, SIV escape from TRIM5α restriction was also observed; therefore, this may not be an effective stand-alone strategy and may require combination with other targets.ImportanceRecent studies suggest that it may be feasible not only to suppress viral replication with antiviral drugs but also potentially to eliminate or "cure" human immunodeficiency virus (HIV) infection. One approach being explored is the use of gene therapy to introduce genes that can restrict HIV replication, including a restrictive version of the host factor TRIM5α. TRIM5 was identified as a factor that restricts HIV replication in macaque cells. The rhesus gene is polymorphic, and some alleles are restrictive for primary SIVsm isolates, although escape mutations arise late in infection. Introduction of these escape mutations into the parental virus conferred resistance to TRIM5 on macaques. The present study evaluated these animals for long-term outcomes and found that TRIM5α restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, suggesting that this could be a valid gene therapy approach that could be adapted for HIV.
| S-EPMC4338887 | biostudies-literature
Project description:Enteropathogenic Escherichia coli (EPEC) was recognized as a common opportunistic pathogen of simian immunodeficiency virus-infected rhesus macaques (Macaca mulatta) with AIDS. Retrospective analysis revealed that 27 of 96 (28.1%) animals with AIDS had features of EPEC infection, and EPEC was the most frequent pathogen of the gastrointestinal tract identified morphologically. In 7.3% of animals dying with AIDS, EPEC represented the sole opportunistic agent of the gastrointestinal tract at death. In 20.8% of cases, it was seen in combination with one or more gastrointestinal pathogens, including Cryptosporidium parvum, Enterocytozoon bieneusi, Mycobacterium avium, Entamoeba histolytica, Balantidium coli, Strongyloides stercoralis, cytomegalovirus, and adenovirus. Clinically, infection was associated with persistent diarrhea and wasting and was more frequent in animals that died at under 1 year of age (P < 0.001, Fisher exact test). The organism was associated with the characteristic attaching and effacing lesion in colonic tissue sections and produced a focal adherence pattern on a HEp-2 assay but was negative for Shiga toxin production as assessed by PCR and a HeLa cell cytotoxicity assay. A 2.6-kb fragment encompassing the intimin gene was amplified and sequenced and revealed 99.2% identity to sequences obtained from human isolates (GenBank AF116899) corresponding to the epsilon intimin subtype. Further investigations with rhesus macaques may offer opportunities to study the impact of EPEC on AIDS pathogenesis and gastrointestinal dysfunction.
| S-EPMC87859 | biostudies-literature