HIV Nef amplifies mechanical heterogeneity to promote immune evasion

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 mechanical properties of infected cells suggests that biophysical mechanisms may also contribute. Here, we show that a subset of CD4+ T cells infected with the human immunodeficiency virus (HIV) resist elimination through a soft phenotype that impairs 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 basal cytoskeletal properties of T cells. Although cells that are sufficiently soft to resist CTLs are relatively rare, this property can be detected in HIV-infected CD4+ T cell clones from people living with HIV, implicating a role for this mechanism in reservoir persistence. These findings define a biophysical paradigm of immune evasion with implications for HIV cure strategies.