HIV-1 and host interactions at molecular level

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

MHHIS research is organized into two overarching HIV-focused projects: 1. Immune development in infants without/with exposure to HIV-1 and the gender effect on inflammation and immune bioprofile in youth without/with HIV. 1.1 Development and maturation of immunoglobulin repertoires in healthy newborns. Purpose. Define the development of immunoglobulin (Ig) transcriptome biodiversity across isotypes among healthy infants during the 1st year of age. Methods. Ig variable heavy chain I(gVH) amplicon transcriptome libraries were generated by PCR from cord blood and peripheral blood cells from infants at 6- and 12-months in comparison to healthy adults. Amplicons were sequenced and analyzed by IgSEQ. Accomplishment. Healthy newborn cord blood B cells displayed the capacity for somatic hypermutation (SHM), affinity maturation and clonality. By 1 yr of age, infant biodiversity reached adult levels, although the extent of infant SHM was still lower than adults. 1.2 Maternal immunity shapes immune development and response in HIV-exposed uninfected (HEU) infants. Purpose. Investigate the effect of prenatal HIV exposure on immune development and response in HEU infants and the relationship with maternal immune milieu. Methods. Immune development in HEU infants was studied by comparing plasma immune biomarkers and peripheral blood cell transcriptome profiles with HIV-unexposed and uninfected (HUU) infants at birth and at 6 months of life. The influence by maternal immune status was evaluated by correlation of plasma biomarker concentrations between mother/newborn pairs. Accomplishment. HEU newborns demonstrated elevated germinal center, immune regulatory, and inflammatory markers in the plasma and down regulated gene expression pathways linked to development and immune response, which was amplified at 6 months of life. In contrast HUU infants showed upregulation of these pathways at 6 months. Correlation analysis indicated maternal influence on their baby’s immune development and response. 1.3 Peripheral blood bioprofiles in young women differed from men without/with HIV. Purpose. Compare young women and men without/with HIV to define molecular bioprofiles associated with gender. Methods. Concentrations of 23 plasma immune biomarkers were measured. Peripheral blood cell mRNA was sequenced and analyzed for differentially expressed genes and related pathways. Accomplishment. Women without HIV compared to men without HIV showed heightened immune activation and inflammation bioprofiles. Gender effects on bioprofiles were amplified in women with undetectable HIV who had multiple activated pathways related to protein synthesis, immune response, oxidation and metabolism compared with men with undetectable HIV. 2.Peripheral blood cell transcriptome bioprofiles with sustained viral suppression on ART and the inflammatory modulatory effect of recreational substance use. 2.1 A multi-omics study of plasma biomarkers and gene expression profile in youth on antiretroviral therapy. Purpose. Antiretroviral therapy (ART) suppresses HIV-1 replication to undetectable level in routine testing but cannot eradicate the virus. Immune biomarkers and host cell gene expression were assessed in virally suppressed youth with HIV compared with non-suppressed youth with HV on ART and youth without HIV to identify bioprofiles as early indicators of viral resurgence and predictors of disease progression. Methods. Plasma biomarkers were analyzed using a machine learning random forest approach. Peripheral blood cell (PBC) transcriptome profile was studied by microarray and analyzed for differentially expressed genes (DEGs) and pathways. Accomplishments. Youth with suppressed levels of HIV, compared to those with non-suppressed levels, had reduced plasma biomarker concentrations of CXCL9 but elevated concentrations of iFABP, and upregulation of DEGs mainly involved in DNA repair and transcriptional regulation. When compared to youth without HIV, virally suppressed youth with HIV showed bioprofiles associated with regulation of apoptosis, post-translation modification and inflammation. While clustering of groups based on transcriptome profiles generally delineated individuals based on viral infection and suppression, some unexpected intra-group heterogeneity highlights the complexity of host-virus interactions and emphasizes the need for nuanced understanding of individual responses to infection and treatment. 2.2 Impact of marijuana and tobacco use on inflammatory pathways in youth and adults with sustained viral suppression on antiretroviral therapy. Purpose. Chronic inflammation and immune activation persist in people with HIV, even with effective ART. Marijuana use is prevalent in people with HIV due to its immunomodulatory properties and potential to reduce inflammation, although long-term effects on health outcomes remain underexplored. This study utilized genome-wide transcriptome analysis to examine the impact of marijuana, alone or with tobacco, on peripheral blood cells (PBC) and monocytes in youth with HIV compared to youth without HIV, and in older adults with HIV. Methods. PBC mRNA was sequenced for youth with HIV, youth without HIV (no substance use), and adults with HIV. Peripheral blood monocytes were isolated from a sub-group of youth with HIV and youth without HIV. Both youth and adults with HIV were virally suppressed on ART, and grouped by substance use (none, marijuana alone or marijuana with tobacco). Transcriptome was sequenced by RNASeq and analyzed for DEGs and pathways. Accomplishments. The transcriptome profile of youth with HIV (no substance use) showed immune activation through macrophage signaling pathways, which were normalized by marijuana use, indicating an anti-inflammatory effect of marijuana. In contrast, marijuana and tobacco co-use activated multiple inflammatory genes and pathways. The monocyte transcriptome profile for marijuana alone identified additional DEGs, involved in Th2 and PPARalpha activation signaling, further validating the anti-inflammatory effect of marijuana, along with its role in maintaining metabolic homeostasis. In adults with HIV who only used marijuana, the PBC transcriptome numerous activated pathways, mainly related to the immune system and cellular processes, while marijuana and tobacco co-use inhibited the innate immune pathways. In summary, in youth with HIV, marijuana alone had anti-inflammatory effects, while co-use with tobacco exacerbated inflammatory pathways. In contrast, in older adults with HIV, prolonged marijuana use perturbed pathways associated with immune activation and cellular growth. 2024 Refereed Conference Abstracts Maternal imprinted immune perturbations in HEU infants persist for 6 months. Yin L, Fischer B, Venturi G, Nepal U, Choudhary S, Shen J, Chang K, Raplee I, Borkar S, Kim-Chang J, De Paris K, Goodenow M, Sleasman J. 31st Conference on Retroviruses and Opportunistic Infections, Denver, CO. Poster No. 02521. Substance use association with neurocognitive function and gene expression in YWH. Borkar SA, Kim-Chang JJ, Yin L, Venturi GM, Shen J, Chang KF, Nepal U, Raplee ID, De Paris K, Sleasman JW, Goodenow MM. 24th NIH NeuroHIV Workshop, Bethesda, MD. Oral presentation. Molecular bioprofiles are distinct for virally suppressed young women or men with HIV on ART. Yin L, Borkar S, Venturi G, Chang K, Nepal N, Shen J, Raplee I, De Paris K, Sleasman J, Goodenow M. 14th International Workshop on HIV & Women, Washington, DC. Poster No. 77. Unraveling gender-related molecular patterns in young women and men with undetectable plasma viremia on ART for targeted care and treatment strategies. Yin L, Borkar S, Venturi G, Chang K, Nepal U, Shen J, Raplee I, De Paris K, Sleasman J, Goodenow M. 25th International AIDS Conference, Munich, Germany. Abstract EPA006.