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Principal Investigator: Maureen Goodenow
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $1,400,080
Funding agency: National Institute of Allergy and Infectious Diseases
Over the past year, our research in MHHIS, NIAID has made progress in the following three projects:
Project 1. HIV exposed uninfected (HEU) infants have pro-inflammatory bioprofiles that correlate with maternal bioprofiles and persist for at least six months. HEU infants have a higher rate of mortality/morbidity, a higher risk for adverse growth, developmental, metabolic, and infectious outcomes, and altered immune response and mtRNA stability. However, how HEU immunity is perturbed and influenced by their mothers HIV immune milieu is largely unexplored, and thus a focus of this study. We hypothesize that there is persistent immune activation and inflammation in HEU babies under the influence of maternal immune status. To address the question, proinflammatory immune pathways from HEU babies and their mothers with HIV pregnant women with HIV (PWH) with/without achieving viral suppression (VS/VNS) on ART were examined in comparison to pregnant women without HIV (PWOH) and their HIV-unexposed uninfected (HUU) babies. Plasma concentrations of 21 immune biomarkers associated with B cell development, macrophage or lymphocyte activation, and inflammation were assessed using Mesoscale Diagnostics multiplex assays. Gestational immune milieu in PWHs was revealed by comparing immune bioprofile of VS and VNS PWH to PWOH. Immune perturbation and persistence in HEU babies born to PWH-VS or to PWH-VNS were investigated by comparing them to HUU at birth, and at 6 months of life. Influence of maternal immune status on their newborns immune profiles was investigated by comparing and correlating immune profiles between mother/baby dyads. Our study demonstrated that, in contrast to PWOH, there is an overall immune activation and inflammation in PWHs even when viral replication is undetectable. HEU babies, independent of their mothers viral status, compared with HUU babies, presented significantly elevated plasma concentrations of biomarkers associated with B cell development, immune activation, pro-inflammation, and ant-inflammation at birth as well as at 6 months of life, indicating an impaired immune priming which persists at least 6 months after birth. Distinctly increased biomarker correlations, particularly pro- and anti-inflammatory biomarkers, between PWHs and their HEU newborns, in comparison to PWOH and their HUU neonates, indicates influences from maternal immune perturbation during pregnancy. In conclusion, HEU babies have impaired early immune priming influenced by maternal immune perturbation.
Project 2. Distinct gene expression signatures are associated with viral suppression in youth with HIV on ART: implications for novel diagnostic or therapeutic targets. HIV replication is regulated by complex interactions between host and viral factors to promote or inhibit HIV replication. ART can suppress HIV replication, viral infection persists. In this study, we examined differential host peripheral blood cell (PBC) gene expression among youth with HIV (YWH) on ART with or without sustained viral suppression and youth without HIV (YWOH). The goal was to identify host cellular factors and pathways unique to YWH with suppressed virus infection and provide insights into molecular interactions associated with control or persistence of viral replication. PBC mRNA was profiled using Affymetrix HG-U133 Plus 2.0 Arrays for 52 participants (27 YWH and 25 YWOH) balanced for age, gender, and race. Among 27 YWH (ages 18-23 years), 19 achieved sustained viral suppression (VS) (< 50 RNA copies/ml plasma), while 8 had detectable viral replication (VNS). Differentially expressed genes (DEGs) were identified using samr package (FC 1.3 and FDR 0.05). Pathway analyses were based on the Gene Ontology database. Our study demonstrated that, in comparison to YWOH, VNS YWH showed 1003 DEGs with 47 perturbed pathways related to interferon signaling and defense against viruses, while VS YWH had 14 perturbed pathways with 367 DEGs, including platelet activation and regulation of serine/threonine protein kinase. Unique hub genes regulating chronic inflammation were observed in YWH with VS compared to YWOH. Direct comparison between VS or VNS YWH identified 131 DEGs involved in DNA repair, RNA processing, and negative regulation of RNA polymerase II transcription pathways, while hub genes obtained from this comparison were found to be associated with viral suppression in youth. In conclusion, youth on ART with VS display distinct molecular profiles that could guide personalized long-acting treatments for prolonged viral suppression and/or lead to development of point-of-care or self-administered diagnostics for HIV resurgence.
Project 3. Effects of alcohol (EtOH) and 9-tetrahydrocannabinol (THC) on early monocyte differentiation: implications for HIV-1 replication. Recreational use of marijuana and/or alcohol can modulate host immune networks in response to pathogens. Short term immune cell exposure to alcohol (EtOH) results in increased expression by genes associated with inflammatory responses, while the main psychoactive component of marijuana, 9-tetrahydrocannabinol (THC), acts as an inflammatory suppressor. In this study, we investigated the molecular consequences of EtOH or THC in EtOH on gene expression profiles during early monocyte differentiation. The goal of this study was to determine when, during monocyte to macrophage differentiation, did treatment contribute to the suppression of ex vivo HIV-1 replication. Human peripheral blood monocytes from five healthy donors were exposed ex vivo to EtOH or THC in EtOH during differentiation for six hours, one day, or three days. Each treatment and time point were individually compared to untreated monocytes. mRNA profiles were analyzed using Affymetrix HTA 2 Arrays. EtOH or THC in EtOH treatment compared to untreated monocytes had similar trends of increasing DEGs over time, although the hub genes and pathways differed. EtOH pathways were associated with proinflammation: activation of Neuroinflammation, Pathogen Induced Cytokine Storm, Role of Chondrocytes in Rheumatoid Arthritis pathways. The hub EtOH DEGs for proinflammation were upregulation of NFB, CXCL8, CXCL10, CCL2, and TLR1/2/6. THC in EtOH pathways were associated with the regulation of immune activation: inhibition of Macrophage Classical/Alternative Activation, Dendritic Cell Maturation, Th1, Multiple Sclerosis, Neuroinflammation, Inhibition of ARE-Mediated mRNA Degradation pathways and activation of IL-10, PD-1/PD-L1 Cancer Immunotherapy, MSP-RON Signaling in Macrophages pathways. The hub DEGs for the THC in EtOH-modulated pathways were a repression of IL10, IFNGR, CD4, SOCS3, TNFR and upregulation of IKBKB. Through time EtOH and THC in EtOH treatments shifted monocyte profiles toward metabolic pathways, including inhibition of Mitochondrial Dysfunction and activation of NRF2-mediated Oxidative Stress Response and Oxidative Phosphorylation. The hub DEGs for metabolic processes were NFE2L2, PPAR, PPAR. By day 3, EtOH treatments no longer perturbed proinflammatory pathways in monocytes, while THC in EtOH treatments continued to regulate or inhibit the monocyte immune activation pathway profile. In conclusion, EtOH exerts a rapid proinflammatory effect on monocyte gene expression early during monocyte to macrophage differentiation, while THC in EtOH demonstrates a continuous inflammation regulatory role as early as six hours after exposure.
Terms: <0-4 weeks old><3-10C><9-ene-Tetrahydrocannabinol><AIDS Virus><AMCF-I><AVP, Type II><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Age><Alcohol Chemical Class><Alcohols><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antiviral Protein, Type II><Ants><Atrophic Arthritis><B-Cell Development><Binding><Biological Markers><Birth><Blast Transformation><Blastogenesis><Blood Cells><Blood Plasma><Blood monocyte><CCL2><CCL2 gene><CD119><CD119 Antigen><CDw119 antigen><CRG-2><CSIF><CSIF-10><CXCL10><CXCL10 gene><CXCL8><Cachectin Receptors><Cell Body><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Cells><Chemokine, CC Motif, Ligand 2><Childhood><Chondrocytes><Chronic><Complex><Cytokine Synthesis Inhibitory Factor><DKFZp547I0610><DKFZp564I0682><DNA Damage Repair><DNA Repair><DNA-Dependent RNA Polymerase II><Data Bases><Databases><Degradation Pathway><Degradative Pathway><Delta-9-Tetrahydrocannabinol><Dendritic Cells><Development><Diagnostic><Disseminated Sclerosis><Expression Signature><GCP1><Gender><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Transcription><Generalized Growth><Genes><Genetic Transcription><Gestation><Goals><Growth><HIV><HIV Infections><HIV-1><HIV-I><HIV-exposed uninfected infant><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Hour><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><IFI10><IFN><IFN-gamma receptor 1><IFN-gammaR><IFN-γR><IFNGR><IFNGR1><IFNGR1 gene><IKBKB><IKK 2 kinase><IKK beta><IL-10><IL-8><IL10><IL10A><IL8><IL8 gene><INP10><IP-10><IkappaB kinase beta><Immune><Immune Cell Activation><Immune Markers><Immune response><Immunes><Immunity><Immunologic Markers><Immunological response><Immunomodulation><Impairment><Individual><Inflammation><Inflammatory><Inflammatory Response><Interferon Gamma Receptor-1><Interferon-Gamma Receptor 1><Interferons><Interleukin 10 Precursor><Interleukin-10><Intermediary Metabolism><Intracellular Communication and Signaling><K60><KIAA0012><LAV-HTLV-III><Lead><Life><Lymphadenopathy-Associated Virus><Lymphoblast Transformation><Lymphocyte Activation><Lymphocyte Stimulation><Lymphocyte Transformation><MCAF><MCP-1><MCP1><MOB-1><Macrophage><Macrophage Activation><Marijuana><Marrow monocyte><Mediating><Messenger RNA><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mitochondria RNA><Mitochondrial RNA><Modern Man><Molecular><Molecular Analysis><Molecular Fingerprinting><Molecular Immunology><Molecular Interaction><Molecular Profiling><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Morbidity><Morbidity - disease rate><Mothers><Multiple Sclerosis><Mφ><NIAID><National Institute of Allergy and Infectious Disease><Network Analysis><Newborn Infant><Newborns><Non-Polyadenylated RNA><Ontology><Outcome><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxidative Stress><PD-1/PD-L1><PD-1/PDL1><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PPAR><Participant><Parturition><Pathogenesis><Pathway Analysis><Pathway interactions><Pb element><Peripheral Blood Cell><Peroxisome Proliferator-Activated Receptors><Plasma><Plasma Serum><Platelet Activation><Pregnancy><Pregnant Women><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><RNA><RNA Expression><RNA Gene Products><RNA Polymerase B><RNA Polymerase II><RNA Processing><Race><Races><Recreation><Regulation><Repression><Research><Reticuloendothelial System, Serum, Plasma><Rheumatoid Arthritis><Ribonucleic Acid><Role><SCYA2><SCYB10><SCYB8><Self Administered><Self Administration><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A2><THC co-use><THC use><TLR1><TLR1 gene><TLR1 protein><TLR1 receptor><TNF Receptor Family Protein><TNF Receptor Superfamily><TNF Receptors><TNFR><TSG-1><Tetrahydrocannabinol><Tetrahydrocannabinol co-use><Tetrahydrocannabinol use><Threonine Kinase><Time><Tissue Growth><Toll-Like Receptor 1><Toll/Interleukin-1 Receptor-Like><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Unscheduled DNA Synthesis><Up-Regulation><Upregulation><Veiled Cells><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Virus-HIV><Youth><Youth 10-21><ages><alcohol abuse therapy><alcohol abuse treatment><alcohol effect><alcohol exposed><alcohol exposure><alcohol treatment><analyze gene expression><anti-cancer immunotherapy><anti-retroviral therapy><anti-retroviral treatment><anticancer immunotherapy><antiinflammatory><antiretroviral therapy><antiretroviral treatment><b-ENAP><bio-markers><biologic marker><biological adaptation to stress><biological signal transduction><biomarker><cancer immunotherapy><cannabis use><compare treatment><cytokine release syndrome><cytokine storm><data base><delta(1)-THC><delta(1)-Tetrahydrocannabinol><delta(9)-THC><delta(9)-Tetrahydrocannabinol><developmental><differential expression><differentially expressed><ethanol effect><ethanol exposed><ethanol exposure><expectant mother><expecting mother><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><gIP-10><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><high risk><host response><immune activation><immune modulation><immune regulation><immune system response><immune-based biomarkers><immune-based cancer therapies><immunologic reactivity control><immunological biomarkers><immunological markers><immunological status><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><insight><insular sclerosis><interferon gamma receptor><mRNA><mRNA Degradation><mRNA Transcript Degradation><marihuana><marijuana use><mitochondrial dysfunction><molecular profile><molecular signature><monocyte><mortality><mtRNA><multiplex assay><multiplex diagnostics><neonate><neural inflammation><neuroinflammation><neuroinflammatory><new diagnostics><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><newborn child><newborn children><next generation diagnostics><novel diagnostics><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><pathogen><pathway><pediatric><peripheral blood><point of care><pregnant mothers><racial><racial background><racial origin><reaction; crisis><response><rheumatic arthritis><rsc786><social role><stress response><stress; reaction><substance use><substance using><transcriptional differences><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome><treatment comparison><trend><vaccine response><vaccine responsiveness><vaccine-induced response><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease><Δ(1)-THC><Δ(1)-tetrahydrocannabinol><Δ(9)-THC><Δ(9)-tetrahydrocannabinol><Δ-9-tetrahydrocannabinol><Δ9-tetrahydrocannabinol>