Immunometabolic regulation in natural HIV-1 control

The elite controllers (EC) are a rare group of people living with HIV-1 infection (PLHIV) that can control viral replication in the absence of antiretroviral therapy for a prolonged time. The mechanisms behind elite control phenotype leading to viral suppression are not fully elucidated. It has also become clear that molecules function in complex and interconnected networks shaping the phenotype of a cell, tissue, or organism. The advancements made in high- throughput technologies and in computational methods enable the investigation of a large set of molecules simultaneously allowing to fingerprint the cross-talks and dynamics of these molecules.

The work presented in this thesis aimed to unravel the immuno-metabolic regulation in PLHIVEC using a data-driven approach where untargeted metabolomics, proteomics and microbiome profiling were applied in combination with targeted immunological and other assays. We observed that PLHIVEC had a distinct plasma and fecal metabolic signature compared to treatment-naïve HIV-1-positive viremic progressors (PLHIVVP) and HIV- negative individuals (HC). Low-level inflammation and antioxidant defense mechanisms at physiological levels seen in plasma and blood cells, together with increased fecal levels of dipeptides and the bacterial genus Prevotella are proposed to be important factors involved in natural control of HIV-1. Furthermore, a unique signature of chemokine receptor expression on immune cells and a specific proteomic profile of CD4+ T cells indicative of a modulated energy metabolism may also play a role in EC phenotype. Altogether these features are suggested to create an unfavorable environment for HIV-1 replication and thus contribute to natural control of the virus.

List of scientific papers

I. Sperk M, Mikaeloff F, Svensson-Akusjärvi S, Krishnan S, Ponnan SM, Ambikan AT, Nowak P, Sönnerborg A, Neogi U. Distinct lipid profile, low- level inflammation, and increased antioxidant defense signature in HIV-1 elite control status. iScience. 2021; 24(2): 102111.
https://doi.org/10.1016/j.isci.2021.102111

II. Sperk M, Ambikan AT, Ray S, Singh K, Mikaeloff F, Diez RC, Narayanan A, Vesterbacka J, Nowak P, Sönnerborg A, Neogi U. Fecal Metabolome Signature in the HIV-1 Elite Control Phenotype: Enrichment of Dipeptides Acts as an HIV-1 Antagonist but a Prevotella Agonist. J Virol. 2021; 95(18): e0047921.
https://doi.org/10.1128/JVI.00479-21

III. Svensson Akusjärvi S, Krishnan S, Jütte BB, Ambikan AT, Gupta S, Rodriguez JE, Végvári Á, Sperk M, Nowak P, Vesterbacka J, Svensson JP, Sönnerborg A, Neogi U. Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individuals. Communications Biology. 2022; 5(1): 357.
https://doi.org/10.1038/s42003-022-03315-x