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Principal Investigator: Melanie Maria Ott
Organization: J. DAVID GLADSTONE INSTITUTES
Fiscal Year: 2024
Award: $915,998
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Recent data suggest that a substantial fraction of the HIV reservoir persisting in the face of antiretroviral
therapy (ART) is transcriptionally active and may contribute to the chronic inflammation observed in people with
HIV (PWH). This is particularly pertinent in elderly PWH, who exhibit additional elevated inflammation and co-
morbidities due to the aging process itself. Surprisingly, immune differences between the sexes prove largest
after the age of 65, an unexpected observation given that the menopausal transition in women (typically occurring
between the ages of 45-55) decreases estradiol to levels similar to those of men. The extent to which biological
sex and sex steroids impact the HIV reservoir and chronic inflammation in elderly PWH has not been sufficiently
studied. In this proposal, we will deeply characterize the transcriptionally-active HIV reservoir in aged ART-
suppressed men and women with HIV, determine how these cells contribute to chronic inflammation, and identify
novel ways to block their ongoing viral gene expression. We will leverage the infrastructure of the MACS/WIHS
Combined Cohort Study (MWCCS), and include not only virally suppressed men and women with HIV, but also
those with non-suppressible viremia (NSV) as extreme cases of HIV transcriptional activity in the face of ART.
In Aim 1, we will use our newly developed single-cell sequencing-based technology, HIV-Seq, to compare the
phenotypes, transcriptomes, and clonal expansion history of transcriptionally-active reservoir cells between
elderly male and female participants, and between different tissue sites from aging women with HIV. In Aim 2,
we will use multiple “omics” technologies (CyTOF, Olink) to test the hypothesis that ongoing HIV gene expression
drives chronic inflammation by fueling expansion of HIV- and CMV-specific CD4+ T cells harboring
transcriptionally-active HIV. In Aim 3, we will identify novel ways to block ongoing HIV gene expression by
targeting the accessory protein Tat, and test the consequences of this blockade in primary cell models and using
patient specimens. Collectively, our aims will help develop strategies to prevent the expansion of the
transcriptionally-active reservoir in aging male and female individuals living with HIV and identify drugs that
durably silence HIV expression in reservoir cells. Our inclusion of post-menopausal women is a notable
innovation, as women have been historically understudied even though they shoulder a large burden of the HIV
epidemic.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Age><Age Years><Aged 65 and Over><Aging><Antigens><Aquadiol><Base Sequence><Biopsy><Blood><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CITE sequencing><CITE-seq><CITEseq><CMV><Cell Body><Cell Line><Cell model><CellLine><Cells><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><Cellular model><Characteristics><Chronic><Clonal Expansion><Cohort Studies><Concurrent Studies><Contracting Opportunities><Contracts><Cytomegalovirus><DNA><Data><Deoxyribonucleic Acid><Differences between sexes><Differs between sexes><Dimenformon><Diogyn><Diogynets><Drops><Drugs><Elderly><Epidemic><Estrace><Estradiol><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogens><Estrone><Exhibits><Female><Gametes><Gene Expression><Gene Transcription><Genetic Transcription><Germ Cells><Germ-Line Cells><Goals><Gonadal Steroid Hormones><HCMV><HIV><History><Human Immunodeficiency Viruses><Immune><Immunes><In Vitro><Individual><Infection><Inflammaging><Inflammation><Infrastructure><LAV-HTLV-III><Lead><Lymphadenopathy-Associated Virus><Measures><Medication><Medicinal Chemistry><Menopause><Modeling><Molecular Target><NIH><National Institutes of Health><Non-Polyadenylated RNA><Nucleotide Sequence><Ovocyclin><Ovocylin><Participant><Pathway interactions><Patients><Pb element><Perimenopausal><Perimenopause><Persons><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Phenotype><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Process><Production><Progynon><Proteins><RNA><RNA Expression><RNA Gene Products><Recording of previous events><Reproductive Cells><Research Specimen><Ribonucleic Acid><Salivary Gland Viruses><Sex Cell><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Shoulder><Single cell seq><Site><Specimen><Strains Cell Lines><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Technology><Testing><Therapeutic Estradiol><Therapeutic Estrogen><Therapeutic Estrone><Tissue Model><Tissues><Trans-Activation of Transcription Protein><Trans-Activator of Transcription of HIV><Transactivating Regulatory Protein><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><United States National Institutes of Health><Viral><Viral Genes><Viremia><Virion><Virus Particle><Virus-HIV><Visit><Woman><above age 65><advanced age><after age 65><after menopause><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><age-related inflammation><aged><aged 65 and greater><aged 65+><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aged ≥65><ages><aging population><aging process><antiretroviral therapy><antiretroviral treatment><assay development><biological sex><candidate validation><cellular indexing of transcriptomes and epitopes by single cell sequencing><co-morbid><co-morbidity><comorbidity><cultured cell line><cytomegalovirus group><drug/agent><following menopause><gene product><geriatric><global gene expression><global transcription profile><gonadal steroids><heavy metal Pb><heavy metal lead><histories><human old age (65+)><immunogen><inflamm-ageing><inflamm-aging><inhibitor><initial cell><innovate><innovation><innovative><lead optimization><male><men><menopause transition><mortality><multiomics><multiple omics><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><nucleic acid sequence><old age><over 65 years><panomics><past menopause><pathway><peri-menopausal><peri-menopause><population aging><post-menopausal><postmenopausal><postmenopausal status><prevent><preventing><programs><resistance mutation><resistant mutation><scRNA-seq><screening><screenings><senior citizen><sex><sex based differences><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><sexual cell><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell next generation sequencing><single cell sequencing><single cell transcriptomic profiling><single-cell RNA sequencing><synergism><tat Protein><therapy adherence><therapy compliance><transcriptome><transition to menopause><transitional menopause><viraemia><viral resistance><viral sepsis><virus resistance><virusemia><≥65 years>