Abstract
Cellular metabolism provides all molecules essential for the cell’s functions including nucleic acids, amino acids and fatty acids, but also energy via glycolysis and mitochondrial respiration (also known as OXPHOS). Viruses hijack these pathways to support the different steps of their replication, making the metabolic state of the infected cell a key factor influencing viral replication. In particular, Human Immunodeficiency virus (HIV) remains latent in resting, metabolically inactive CD4 T lymphocytes but actively replicates in activated CD4 T cells. In these cells, enhanced glycolysis and OXPHOS, and access to the major carbon sources such as glucose and glutamine are required for infection. Here, we took advantage of the recently developed Human Plasma-Like Medium (HPLM), that mimics physiological plasma concentration of metabolites, including carbon sources, to investigate how this physiologic environment would modulate HIV-1 infection of primary CD4 T cells. Using CD4 T cells activated in the conventional culture medium (RPMI) or HPLM, we show that HPLM enhanced HIV-1 infection despite similar levels of cell activation, proliferation and expression of viral receptor. Specifically, HPLM increases the reverse transcription step of the HIV-1 replication cycle. In contrast with previous studies performed in RPMI only, this increased infection in HPLM correlated with decreased glycolysis and mitochondrial metabolism, reflecting the low concentration of glucose and glutamine in this medium. Adjusting glucose and glutamine concentrations in RPMI or decreasing energy metabolism using chemical inhibitors did not increase infection to levels similar to HPLM suggesting that other metabolic pathways are involved. Taken together, this study shows that the metabolic state of activated CD4 T cells in a physiologically relevant environment is more permissive to HIV-1 infection than previously suggested by studies using conventional cell culture media. Our study demonstrates the importance of physiologic culture conditions to study viral infections while also highlighting the importance of non-energetic cell metabolism in HIV-1 infection.