The human plasma amino acids balance favours HIV replication in primary CD4 T lymphocytes

Cellular metabolism supports all viral replication steps and the metabolic state of infected cells is therefore a key factor influencing viral infections. Human Immunodeficiency virus (HIV) remains latent in resting CD4 T lymphocytes but actively replicates in activated CD4 T cells due to enhanced energy metabolism. Here, using the recently developed Human Plasma-Like Medium (HPLM) that mimics physiological plasma concentration of metabolites, we investigated how this near-physiologic environment modulates HIV-1 infection in primary CD4 T cells. Compared to the conventional culture medium (RPMI), HPLM enhanced HIV-1 infection in CD4 T cells despite similar levels of cell activation, proliferation and expression of viral receptor. In contrast with previous studies in RPMI, HPLM increased infection while decreasing energy metabolism and affecting other non-energetic metabolic pathways. Adjusting levels of several metabolites in RPMI and HPLM, we uncovered that the amino acids balance rather than the energy metabolism favoured HIV-1 replication in this system. Overall, our study used near-physiological conditions to better define metabolic dependencies of viral infections and highlights previously overlooked non-energetic metabolism pathways important for HIV-1 infection.