The Gabuzda lab studies HIV pathogenesis and comorbidities using genetic, biochemical, metabolomic, computational, and systems biology approaches. Current projects focus on: 1) virus-host interactions that impact immune control, inflammation, comorbidities, accelerated aging, and frailty; 2) mechanisms of viral replication in the CNS, HIV-associated neurological disorders, and cognitive decline; 3) biomarkers predictive for development of HIV-associated neurological disorders, depression, and medical comorbidities; 4) cancer risk and etiologies in populations with HIV; 5) role of exosomes and other extracellular vesicles in cell-cell communication and pathophysiology. The lab has expertise in bioinformatics, computational, and systems biology approaches including generation, analysis, interpretation, and visualization of large datasets, 'omics (transcriptome profiling, multiplex biomarker profiling, metabolomics, proteomics, etc.) and using R and other software for data integration, network prediction, and pathway analysis. The lab also uses machine learning to identify features predictive of class membership and outcomes and has expertise in analyzing longitudinal data, modeling, and risk prediction.
Molecular biology of HIV replication We published studies providing key insights into molecular biology and functional roles of the HIV Vif, Nef, and envelope proteins. In early work, we showed that Vif is required during late stages of infection, and requirement for Vif differs among cell lines, leading to classification of cells as nonpermissive and permissive for replication of Vif-deficient viruses and providing first evidence that Vif acts through a cell-specific factor, now known to be APOBEC3G. We then characterized other aspects of Vif biochemistry and biology, publishing many papers in the field including some of the first to elucidate mechanisms by which Vif overcomes the antiviral activity of APOBEC3G by targeting it for degradation via the ubiquitin-proteasome pathway, studies characterizing a novel SOCS-box in Vif that targets APOBEC3G for proteasomal degradation, and high throughput screens identifying small molecule inhibitors of Vif-APOBEC3G that protect APOBEC3G from Vif-mediated degradation. In other papers, we elucidated the biology of HIV Nef, including novel interactions with cellular signaling pathways in resting T-cells and its association with host cell proteins that mediate cell-cell communication during virus replication. We also published many studies on functions of the HIV envelope glycoproteins that provided new insights into Env interactions with CD4 and coreceptors and mechanisms mediating virus entry, cell tropism, Env-mediated fusion, and cytopathicity.
Envelope-receptor interactions that determine HIV neurotropism A major focus of our work has been to understand mechanisms of HIV neurotropism and virus entry and persistence in the CNS. We published one of the first studies demonstrating that macrophages and microglia are the main cellular reservoirs of HIV in the brain. We then showed that CCR5 is the primary coreceptor used together with CD4 for HIV entry in the CNS and that CCR5 ligands inhibit infection of microglia. Our subsequent work showed that neurovirulent primary HIV strains have reduced dependence on CCR5 and CD4 levels for virus entry, and such strains are frequently present in the brains of individuals with virus replicating in brain and HIV-associated dementia, representing a pathogenic viral phenotype that contributes to neurodegeneration when viral replication is not suppressed. These findings provided fundamental insights into mechanisms of HIV entry in the CNS and suggested that CCR5 inhibitors may be a useful therapeutic approach for HIV-associated neurological disease.
Monocytes/macrophages in HIV pathogenesis The lab made several key contributions to understanding the role of activated monocytes and macrophages in disease pathogenesis. In addition to elucidating the role of macrophages and microglia as reservoirs for HIV replication in the brain, we published one of the first studies to characterize levels and regulation of CCR5 expression on primary human macrophages and microglia. In subsequent work, we showed that the CD16+ subset of activated monocytes express fractalkine receptor CX3CR1 and are preferentially recruited to endothelial cells in blood vessels via fractalkine (CX3CL1)-CX3CR1 interactions, providing insights into mechanisms involved in vascular and tissue injury during inflammatory conditions. In addition, we published the first studies demonstrating the ability of CD16+ monocytes and monocyte-derived macrophages to promote HIV infection of resting T cells. We also published the first study to characterize the global transcriptome of CD16+ and CD16- monocyte subsets, providing novel insights into their developmental origin and distinct biological and pathological functions.
NeuroHIV pathogenesis and biomarkers The lab published many studies that increased understanding of mechanisms involved in neuroHIV pathogenesis. In addition to characterizing mechanisms of virus entry and replication in the brain, we identified mechanisms by which unsuppressed viral replication in the brain promotes macrophage/microglia activation and neurodegeneration. We published the first study demonstrating association between microbial translocation and elevated LPS, monocyte activation, and increased risk of cognitive impairment in HIV+ individuals with advanced disease. In subsequent work, we identified soluble CD14, a monocyte activation marker, as a biomarker associated with cognitive impairment in HIV+ individuals with advanced disease and unsuppressed viral replication. We also identified biomarker profiles of ongoing intrathecal inflammation in HIV+ individuals on ART and predictors of viral escape in the cerebrospinal fluid (CSF). These studies elucidated mechanisms that contribute to cognitive impairment and viral persistence in the CNS despite current therapies and identified biomarkers being used in clinical studies of cognitive impairment or depression in people with HIV.
Metabolomics and proteomics of HIV/AIDS and associated comorbidities The lab has substantial expertise in using metabolomics, proteomics, and other ‘omics technologies to reveal insights into pathogenesis of HIV/AIDS and comorbidities. We published the first study to characterize the plasma metabolome of HIV+ individuals on suppressive ART, identifying metabolite alterations indicative of dysregulated lipid metabolism and linking these alterations to markers of inflammation and hepatic dysfunction. In subsequent work, we characterized the CSF metabolome of HIV+ individuals with cognitive impairment, demonstrating metabolite alterations indicative of glial inflammation, altered metabolic waste clearance, and accelerated aging. In other work, we characterized the plasma metabolome associated with depression in people with and without HIV, demonstrating associations between interferon responses, tryptophan catabolism, and depressive symptoms in HIV+ individuals. In another study, we identified a novel biotype of depression in ART-treated HIV+ individuals characterized by low neuroactive steroids. Recently, we used proteomics to characterize protein cargo of CSF extracellular vesicles in HIV+ individuals in relation to neuroinflammation and stress responses in HIV-associated cognitive impairment. Other ongoing work includes the analysis of exosomes and other extracellular vesicles and how they are related to immune activation, oxidative stress, and comorbidities.
Programs The Gabuzda Lab is affiliated with the following Programs and Centers within the Harvard research community including the Harvard Center for AIDS Research (CFAR), Dana-Farber/Harvard Cancer Center (DF/HCC), and Harvard Virology Program. The lab is also affiliated with the Multicenter AIDS Cohort Study (MACS), a longitudinal study of over 6,000 men enrolled at 4 sites since 1984 and collaborates with investigators with the ALIVE cohort study at Johns Hopkins and NNTC consortium (MSSM, UCLA, UT Galveston, and UCSD).