Type 1 interferon resistance in the HIV-1 envelope glycoprotein

A key attribute for the transmission of HIV-1 between individuals is the virus's intrinsic resistance to the antiviral activities of type-1 interferons (IFN-I). Transmitted viruses have a higher resistance to IFN-I than those isolated from the recipient partner 6 months later. The effects of IFN-I on HIV-1 replication are mediated by interferon-induced genes (ISGs), several of which directly inhibit stages of the virus lifecycle. The Interferon-Induced Transmembrane Proteins (IFITMs) are broadly-acting ISGs that target the cell entry process that is mediated by its envelope glycoprotein (Env). We have found that transmitted HIV-1 strains are IFITM resistant but sensitivity increases over time as Env adapts to escape host antibody responses. Insensitivity to IFITMs contributes substantially to the IFN-I resistance of the transmitted virus. Preliminary data suggests that IFITM/IFN resistance of Env correlates with the structural rearrangements it must undergo when it binds to its receptor CD4. The more stable the Env, the more IFITM resistant. Thus the transmitted Env is structurally constrained by the need to be IFN-resistant. Since this is the structure that an effective vaccine needs to protect against, understanding the molecular basis of these constraints is essential. In this project the student will:

. use molecular and cellular virology, FRET-based assays and super-resolution microscopy to study how the clustering and dynamics of Env/receptor interactions contribute to IFN/IFITM resistance (Yrs 1-2).
. using patient samples from well characterized cohorts, clone and characterize Envs from patients longitudinally and determine how neutralizing antibody escape leads to loss of IFN resistance in Env (Yrs 2-3).