HIV-1 Gag-protease-driven replicative capacity influences T-cell metabolism, cytokine induction, and viral cell-to-cell spread

This study explored how differences in HIV‑1’s ability to replicate (called replicative capacity) affect the behaviour of infected immune cells and the way the virus spreads between them. Scientists built modified viruses using patient‑derived gag‑protease genes from HIV‑1 subtypes B and C and tested them in laboratory T cells. These genes influence how efficiently the virus copies itself and how it interacts with host cells.

They found that viruses with high replicative capacity (especially subtype B‑derived) had a greater ability to spread from cell to cell and caused infected T cells to take up more glucose and change how they use nutrients. These high‑capacity viruses also triggered higher levels of certain signalling proteins, including IL‑7 and platelet‑derived growth factor, which can affect immune function. By contrast, viruses with lower replicative capacity (more common in subtype C) induced higher levels of other immune signalling proteins like TNF‑α, IL‑8, and IL‑13 and were less efficient at spreading between cells.

The study also showed that higher replicative capacity was linked with changes in how mitochondria (the cell’s energy generators) function and how cells consume nutrients like glutamine. These differences in cell metabolism and signalling may help explain why some HIV strains lead to faster disease progression or stronger immune activation.

Overall, the findings suggest that the virus’s intrinsic replication ability influences how infected T cells respond, how the virus spreads, and potentially how the disease develops, offering insights that could guide future therapeutic strategies to limit virus spread or dampen harmful immune responses.