HIV Nef amplifies mechanical heterogeneity to promote immune evasion
Leyre, L.; Mustapha, F.; Herrera, A.; Lee, E.; Huntsman, E.; Zumbo, P.; Weiler, J.; Sinha, P.; Naing, E.; Smith, C.; Kovacs, C.; Galiano, M.; Wahman, N.; Betel, D.; Clayton, K. L.; Huse, M.; Jones, R. B.
Show abstract
Intracellular pathogens must evade cytotoxic immunity to establish persistent infection. Although immune escape is typically viewed through a biochemical lens, the ability of certain pathogens to alter the mechanical properties of infected cells suggests that biophysical mechanisms may also contribute to the process. Here, we show that a subset of CD4+ T cells infected with the human immunodeficiency virus (HIV) resist elimination through a soft phenotype that inhibits killing by mechanosensitive cytotoxic T lymphocytes (CTLs). This phenotype arises from the combined effects of the HIV virulence factor Nef, which remodels the actin cytoskeleton, and intrinsic heterogeneity in the basal cytoskeletal properties of infected T cells. Pharmacological or genetic perturbations that reverse Nef signaling to the cytoskeleton or that stiffen the filamentous-actin cortex sensitize infected cells to CTL-mediated lysis. Taken together, these findings define a novel, biophysical paradigm of immune evasion with implications for HIV cure strategies.
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