A Subset of HIV-1 Controllers Lack Cortical Actin Disruption Indicative of ARP2/3 Inhibition

Abstract

A small fraction of people living with HIV-1 suppress viral replication naturally and exhibit delayed or absent disease progression without antiretroviral therapy, yet the underlying mechanisms of viral control remain elusive. Despite the known role of HIV-1 in disrupting the actin cytoskeleton and altering cell migration and morphology within tissues, the molecular underpinnings that link viral actin disruption to disease progression have yet been linked to disease progression. We have previously shown through ultrastructural and time-lapse imaging that HIV-1 mediated actin disruption mirrors ARP2/3 inhibition within primary CD4+T cells of normal progressors and uninfected controls. Infected CD4+T cells from these two cohorts routinely exhibit two unique phenotypes when migrating. The first morphological difference is a sharp elongated and pointed lamellipodial tip, “Rhino” phenotype, distinct from the broad leading edge of uninfected cells. The second morphological difference is a non-apoptotic polarized blebbing at the lamellipodia of infected cells. These two pathological morphologies can be recapitulated in uninfected cells with chemical inhibitors of the ARP2/3 complex and are temporally linked based on the differentiation status of the T cell. These effects are dampened, but not totally eradicated, in the absence of the HIV-1 Nef protein. In contrast to normal progressors, infected cells from two out of the three HIV-1 controllers tested in this study did not exhibit these cellular pathologies. The profound impact of ARP2/3 inhibition on immunopathogenesis within genetic and infectious diseases provides context into how HIV-1 may cause cellular and systemic immune dysfunction in normal progressors. The mechanically destabilized cellular cortex may also provide a selective protection for viral genome-intact and long-lived defective reservoirs from cell-mediated killing by host CD8+T cells and NK cells. This mechanical instability is absent in some HIV-1 controllers. Restoring ARP2/3 function and cortical actin integrity in people living with HIV-1 infection is a new avenue of investigation to eradicate HIV-1 infected cells from the body.