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Principal Investigator: Aida Sivro
Organization: CENTRE/AIDS PROGRAMME/RES/SOUTH AFRICA
Fiscal Year: 2024
Award: $122,682
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Previously, we carried out large-scale analysis of mucosal cytokines and HIV acquisition in high-risk women from
KwaZulu-Natal, South Africa, enrolled as part of the CAPRISA 004 TFV 1% gel study (n = 774). Using a
prospective cohort design, we validated our previous finding that inflammatory cytokines increase the risk of HIV
acquisition. Of the cytokines associated with increased risk, one of the strongest associations was observed for
the key type I IFN, IFN2 (p = 10E-6). Women in upper quartile for IFN2 were at 4-fold greater risk of acquiring
HIV, compared to women in the lowest quartile (HR 3.9, 95% CI 1.7-9.1). On the surface this seems counter-
intuitive, as type I IFN have strong anti-HIV effects both in vitro and when given in vivo as a therapeutic or
prophylactic in non-human primate model. To reconcile these observations, we hypothesize that chronic type
I IFN upregulation in the female reproductive tract (FRT) leads to dysregulation of IFN signaling, resulting
in downregulation of antiviral genes, increase in generalized inflammation and increase in susceptibility
of target cells at the site of infection. This hypothesis would provide an explanation as to why a classical anti-
viral program that should be protective actually leads to higher rates of HIV acquisition. Utilizing samples from
the ongoing CAPRISA 018 tenofovir alafenamide (TAF) sub-dermal implant trial, we will determine whether
prolonged IFN2 upregulation in the FRT leads to decreased IFN responsiveness and IFN-stimulated gene (ISG)
expression in genital immune cells. Next, we will formally test if the chronic increase in IFN2 expression and
ISG downregulation correspond to breakthrough HIV infections in young women enrolled in CAPRISA 018.
Finally, we will use an in vitro PBMC model to determine the mechanism by which prolonged IFN upregulation
leads to ISG downregulation and subsequent increase in HIV risk.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Anti-viral Response><Biometrics><Biometry><Biostatistics><COVID-19><COVID-19 virus><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chronic><Clinical Research><Clinical Study><Clinical Trials><CoV-2><CoV2><Cohort Analyses><Cohort Analysis><Cohort Studies><Concurrent Studies><Coronavirus Infectious Disease 2019><Down-Regulation><Enrollment><Epidemiology><Gel><Gene Down-Regulation><Gene Expression><Gene Transcription><Generations><Genetic Transcription><Genital Organs><Genitalia><HIV><HIV Infections><HIV risk><HTLV-III Infections><HTLV-III-LAV Infections><High Risk Woman><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IFN><Immune><Immune response><Immunes><Immunological response><Immunology><Impairment><Implant><In Vitro><Infection><Inflammation><Inflammatory><Interferon Type I><Interferons><International><Intracellular Communication and Signaling><Investigators><LAV-HTLV-III><Link><Location><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Measures><Mediating><Modeling><Mucosa><Mucosal Tissue><Mucous Membrane><PBMC><Pathogenicity><Pathway interactions><Peripheral Blood Mononuclear Cell><Phenotype><Predisposition><Prevention><Prospective cohort><RNA Expression><Research Personnel><Researchers><Rhesus Macaque><Rhesus Monkey><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Site><South Africa><Surface><Susceptibility><Systemic infection><Tenofovir><Testing><Therapeutic><Transcription><Transcription Repression><Transcriptional Repression><Transmission><Up-Regulation><Upregulation><Viral><Viral Diseases><Viral Genes><Viread><Virus><Virus Diseases><Virus-HIV><Woman><Wuhan coronavirus><at-risk females><at-risk women><biological signal transduction><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><desensitization><design><designing><enroll><epidemiologic><epidemiological><female genital tract><female reproductive tract><females at high risk><gene repression><hCoV19><high risk females><host response><immune system response><immunopathology><immunoresponse><in vitro Model><in vivo><multidisciplinary><nCoV2><non-human primate><nonhuman primate><pandemic><pandemic disease><pathway><permissiveness><prevent><preventing><programs><prophylactic><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><subcutaneous><subdermal><transcriptomics><transmission process><viral infection><virus infection><virus-induced disease><women at high risk><women's genital tract><women's reproductive tract><young woman>