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Principal Investigator: Scott A. Handley
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $819,227
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The majority of HIV worldwide is transmitted following heterosexual intercourse and women are twice as likely
to contract HIV from heterosexual sex than men. Mucosal tissues in the female genital tract (FGT) therefore
represent the frontline of transmission since they are the site at which HIV infection is first established in most
incident cases. FGT microbiota composed of diverse communities of bacteria with low Lactobacillus abundance
are associated with elevated mucosal inflammation, increased numbers of cervical HIV target cells, and over
four-fold higher risk of HIV acquisition. In our prior work with the FRESH (Females Rising through Education,
Support and Health) study, we demonstrated that these high-risk bacterial communities are present in over 60%
of young, healthy, black South African women. The specific mechanisms by which vaginal microbiota contribute
to HIV acquisition risk remain unknown. To address these knowledge gaps, we will utilize samples from 1200
FRESH participants with longitudinal blood and genital sampling, including pre- and post-infection samples from
102 women who went on to acquire HIV. In Aim 1.1 we will generate multi-omics datasets characterizing vaginal
microbiota utilizing metagenomics, metatranscriptomics, fungal internally transcribed spacer (ITS) sequencing,
culturomics, microbial whole genome sequencing (WGS), and metabolomics. We will complement this in Aim
1.2 with a comprehensive characterization of the host FGT mucosal environment by assessing genital
inflammatory chemokines and cytokines, cervical flow cytometric cell phenotype, and cervical single cell RNA
sequencing (scRNAseq) profiles, combined with in-depth behavioral and demographic metadata. These complex
multi-omics datasets and metadata will then be integrated in Aim 1.3 following critical quality control,
transformation, and imputation of data from each modality. Modern supervised integration techniques will be
used to identify multi-omics profiles predictive of genital inflammation and HIV acquisition. Novel candidate
vaginal bacterial strains, functions, and/or metabolites will then be validated in Aim 2 using innovative in vitro
and in vivo models, including an organ-on-a-chip model, cervical and vaginal organoids, and a humanized mouse
model. [In addition, we will test candidate features and hypotheses based upon our extensive preliminary data
and established work in the field]. Overall, this project will identify specific bacterial strains and molecules, along
with host cellular lineages and sensing pathways, that mediate microbiota-induced genital inflammation and
increased HIV acquisition risk. It will also validate much needed novel model systems that test the interactions
of microbiota, host, and HIV to provide critical resources to develop the mechanistic understanding needed to
advance the field.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Africa South of the Sahara><African Females><African Women><Age><Anaerobic Bacteria><Area><Bacteria><Bacterial Infections><Behavioral><Biologic Models><Biological Models><Biostatistical Methods><Blood><Blood Reticuloendothelial System><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cells><Cervical><Cervix><Cervix Uteri><Chemotactic Cytokines><Clinical><Collaborations><Communities><Complement><Complement Proteins><Complex><Contracting Opportunities><Contracts><Data><Data Set><Education><Educational aspects><Environment><Epithelial Cells><Exposure to><Female><Functional Metagenomics><Gene Transcription><Genetic Transcription><Genital Organs><Genitalia><HIV><HIV Infections><HIV-2><HIV-II><HIV2><HTLV-III Infections><HTLV-III-LAV Infections><HTLV-IV><Health><Heterosexuals><History><Homologous Chemotactic Cytokines><Human Immunodeficiency Virus Type 2><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human T-Lymphotropic Virus Type IV><Human immunodeficiency virus 2><Immune><Immunes><Immunology><In Vitro><Incidence><Infection><Inflammation><Inflammatory><Intercrines><Knowledge><LAV-2><LAV-HTLV-III><Lactobacillus><Libraries><Lymphadenopathy-Associated Virus><Measures><Mediating><Mediator><Membrane><Metadata><Metagenomics><Microbe Genome Sequencing><Microbial Genome Sequencing><Modality><Model System><Modeling><Modernization><Mucosa><Mucosal Inflammation><Mucosal Tissue><Mucositis><Mucous Membrane><Multiomic Data><Organoids><Participant><Pathogenesis><Pathway interactions><Phenotype><Play><Predisposition><Prevalence><Productivity><Quality Control><RNA Expression><Recording of previous events><Research><Research Resources><Resolution><Resources><Risk><Risk Factors><Role><SIS cytokines><Sampling><Seminal><Site><South African><Sub-Saharan Africa><Subsaharan Africa><Susceptibility><T4 Cells><T4 Lymphocytes><Techniques><Testing><Tissues><Transcription><Transmission><Uterine Cervix><Vagina><Virus-HIV><Visualization><Woman><Work><ages><anaerobe><analyze microbiome><bacteria infection><bacterial community><bacterial disease><chemoattractant cytokine><chemokine><cohort><complementation><cytokine><experience><female genital tract><female reproductive tract><genital secretion><high risk><histories><human disease><humanized mice><humanized mouse><in vivo Model><inhibitor><innovate><innovation><innovative><membrane structure><men><meta data><metabolism measurement><metabolomics><metabonomics><metatranscriptomics><microbial consortia><microbial flora><microbial genomics><microbial host><microbial whole genome sequencing><microbiome><microbiome analysis><microbiota><microbiota composition><microflora><mouse model><multiomics><multiple omic data><multiple omics><multispecies consortia><murine model><new approaches><novel><novel approaches><novel strategies><novel strategy><organ on a chip><organ on chip><panomics><pathway><prevent><preventing><reproductive><resolutions><scRNA-seq><sex><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><transmission process><vagina infection><vagina microbiota><vaginal biome><vaginal flora><vaginal infection><vaginal microbial community><vaginal microbicide><vaginal microbiome><vaginal microbiota><vaginal microflora><women's genital tract><women's reproductive tract><young woman>