HIV-1 and host interactions at molecular level

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

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.