Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multi-omics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and their association with disease severity. We used multi-omics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell line models along with immune phenotyping of metabolite transporters in patient blood to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multi-omics data to regulate the viral reproduction in vitro . COVID-19 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, GLUT1, in CD8 + T-cells, intermediate and non-classical monocytes, and amino acid transporter, xCT, in classical, intermediate, and non-classical monocytes. In in vitro lung epithelial cell (Calu-3) infection model we found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that SARS-CoV-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

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Summary HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who can suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This study aimed to investigate host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naïve viremic progressors (VP) as well as HIV-negative individuals (HC) to get insights into EC phenotype. Metabolites belonging to antioxidant defense had higher levels in EC relative to VP, whereas inflammation markers were increased in VP compared with EC. Only four plasma proteins (CCL4, CCL7, CCL20, and NOS3) were increased in EC compared with HC, and CCL20/CCR6 axis can play an essential role in EC status. Our study suggests that low-level inflammation and oxidative stress at physiological levels could be important factors contributing to elite control phenotype.

A Phase I HIV-1 vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009 to test a subtype C prophylactic vaccine in a prime-boost regimen comprising of a DNA prime (ADVAX) and MVA (TBC-M4) boost. The trial demonstrated that the regimen was safe and well tolerated and resulted in enhancement of HIV-specific immune responses. Preliminary observations on vaccine-induced immune responses were limited to analysis of neutralizing antibodies and IFN-γ ELISPOT response. The present study involves a more detailed analysis of the nature of the vaccine-induced humoral immune response using specimens that were archived from the volunteers at the time of the trial. Interestingly, we found vaccine induced production of V1/V2 and V3 region-specific antibodies in a significant proportion of vaccinees. Variable region antibody levels correlated directly with the frequency of circulating T follicular helper cells (Tfh) and regulatory T cells (Treg). Our findings provide encouraging evidence to demonstrate the immunogenicity of the tested vaccine. Better insights into vaccine-induced immune responses can aid in informing future design of a successfulHIV-1 vaccine.