The combinatorial effects of Opiates and the emerging promoter-variant strains of HIV-1 subtype C on HIV neuropathogensis and latency

阿片类药物和新出现的 HIV-1 C 亚型启动子变异株对 HIV 神经发病和潜伏期的联合影响

• 批准号: 9982822
• 负责人: Shilpa J. Buch
• 金额: $ 71.88万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982822
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Astrocytes; Binding Sites; Biological; Brazil; CD4 Lymphocyte Count; Cell Line; Central Nervous System Diseases; China; Competence; Country; Coupled; Disease Management; Disease Progression; Drug abuse; Drug usage; Epidemic; Evolution; Generations; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Transcription; Grant; HIV; HIV Infections; HIV-1; Hepatitis C virus; Heroin; Human; Immune System Diseases; Immune response; In Vitro; India; Infection; Integration Host Factors; Interruption; Lead; Longitudinal Studies; Macaca; Macaca mulatta; Mediating; Molecular; Molecular Virology; Monitor; Mutation; NF-kappa B; Neuropathogenesis; Nucleotides; Opiate Addiction; Opioid; Organ; Pathogenesis; Pathogenicity; Peripheral Blood Mononuclear Cell; Plasma; Play; Prevalence; Property; Publications; Reporting; Research Personnel; SIV; Site; South Africa; Substance abuse problem; Variant; Vertebral column; Viral; Viral Load result; Viral reservoir; Virus; Virus Latency; Virus Replication; Western World; attenuation; base; cell mediated immune response; combinatorial; comorbidity; drug abuser; env Genes; fitness; immune activation; injection drug use; insight; opioid abuse; opioid use; promoter; public health relevance; simian human immunodeficiency virus; transcription factor; viral fitness; virus genetics

 DESCRIPTION: Drug abusers account for a substantial proportion of AIDS cases globally. In fact, approximately 10% of new HIV infections worldwide are attributable to injecting drug use, often of an opiate such as heroin. HIV clade C viruses are responsible for nearly half of the global infections and more than 95% of the infections in India. The innate ability of clade C in establishing an expanding epidemic could be ascribed to its unique biological properties, coupled with co-morbidity of drug abuse, which in turn, could influence the HIV LTR genetic polymorphism. We have recently demonstrated the emergence of 4 NF-κB site promoter variant strains in the subtype C in India. The variant viral strains acquire the molecular strategy of attaining an additional NF-κB (3 sites in the wild type & 4 in the variant strains) or RBEIII (onein the wild type & 2 in the variant strains) binding sites (TFBS) leading to enhanced transcriptional potency of the viral promoter. The TFBS duplication is associated with rapid expansion of the variant virus strains in India over the past decade. In fact, the prevalence of the 4-κB strains i India has increased from 1-2% during 2000-2003 to a staggering 30-35% a decade later. The ability to duplicate the NF-κB motifs appears to be unique to subtype C. Based on these observations, we hypothesize that 4-κB strains of subtype C are more infectious leading to increased immune activation, end-organ pathogenesis and latency in the context of opiates. No systemic studies have assessed the impact of viral variant generation on disease progression, and/or end-organ involvement specifically in the CNS. Such longitudinal studies can only be possible in an animal model of HIV infection and opiate abuse. This proposal brings together investigators with unique strengths in molecular virology, macaque pathogenesis and substance abuse to answer these crucial questions while also addressing the relevance in the context of clade B and C viruses. Specifically, two aims are proposed. SA1: To assess the in vitro replication competence of SHIV clones containing 1, 2, 3 or 4 NF-κB binding sites in the promoter as well as env sequences of both clades B and C viruses. SA 2a: To assess the immune responses and disease pathogenesis in Indian rhesus macaques infected with the SHIV clones (clade B vs. C viruses - generated in SA1) in the absence or presence of ART & opiate dependence. SA 2b: To evaluate the influence of the NF-kB number on viral latency in the presence of ART and opiates.



项目成果

An emerging and variant viral promoter of HIV-1 subtype C exhibits low-level gene expression noise.

• DOI: 10.1186/s12977-021-00572-2
• 发表时间: 2021-09-19
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Ali H;Bhange D;Mehta K;Gohil Y;Prajapati HK;Byrareddy SN;Buch S;Ranga U
• 通讯作者: Ranga U

Systems biology analyses reveal enhanced chronic morphine distortion of gut-brain interrelationships in simian human immunodeficiency virus infected rhesus macaques.

• DOI: 10.3389/fnins.2022.1001544
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Olwenyi, Omalla A.;Johnson, Samuel D.;Bidokhti, Mehdi;Thakur, Vandana;Pandey, Kabita;Thurman, Michellie;Acharya, Arpan;Uppada, Srijayaprakash;Callen, Shannon;Giavedoni, Luis;Ranga, Udaykumar;Buch, Shilpa J.;Byrareddy, Siddappa N.
• 通讯作者: Byrareddy, Siddappa N.