Manipulation of immunometabolism by HIV — accessories to the crime?

•Host restriction factors exploit metabolic dependencies to limit HIV replication.•HIV accessory proteins manipulate cellular metabolism and counteract restriction.•Conflict between SAMHD1 and Vpx regulates the dNTP pool for reverse transcription.•Vpu and Nef downregulate cell surface transporters to control the nutrient supply.•Targeting by HIV identifies critical pathways in T-cell immunometabolism.

Evolutionary pressure has produced an ‘arms race’ between cellular restriction factors (limiting viral replication) and viral proteins (overcoming host restriction). The host factors SAMHD1 and SLFN1 patrol metabolic bottlenecks required for HIV replication. Conversely, the HIV accessory proteins Vpx, Vpu and Nef manipulate cellular metabolism to enable viral replication. Recent work identifying Vpu-mediated downregulation of the alanine transporter SNAT1 and Nef-mediated downregulation of the serine carriers SERINC3/5 has uncovered the importance of HIV manipulation of the amino acid supply. Interference with CD4+ T-cell amino acid metabolism suggests a novel paradigm of viral immunomodulation, and signposts fundamental aspects of lymphocyte biology.