The human immunodeficiency virus (HIV) wears one of the most distinctive coats in all of microbiology—and one of the slipperiest. What makes the virus so difficult to detect is its ability to change the structure of its envelope.
HMS researchers have worked out the structure of a hidden, more-conserved region on this notoriously changeable coat—a finding that could answer a longstanding mystery. Though antibodies rarely attack HIV, there is one that can block infection, but it has been unclear how. It now appears that this antibody gains unexpected access to the newly described region. The findings, reported in the January Immunity, could boost efforts to derive an antibody-based vaccine against HIV.
The HIV coat—frequently depicted as a layer of spikelike structures—consists of two proteins, glycoprotein 120 (gp120)—the head—and glycoprotein 41 (gp41)—the actual spike. Mikyung Kim, Ellis Reinherz, and colleagues focused on a region at the base of gp41, the membrane proximal ectodomain region (MPER). Using a trio of imaging techniques—nuclear magnetic resonance imaging (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR)—they discovered that MPER assumes an L-shaped structure consisting of two helical arms joined by a flexible hinge. The hinge, along with parts of the arms, is buried in the viral membrane. Upon contact with a host CD4 cell, the MPER hinge flips open, essentially allowing the virus to get a foothold on the cell.
Targeting such a wily protein would appear to be a difficult feat. Yet it now appears that at least one antibody does exactly that, the so-called broadly neutralizing antibody (BNAb) 4E10. Using their imaging methods, Reinherz, an HMS professor of medicine, Kim, an HMS instructor in medicine, both at Dana–Farber Cancer Institute, and colleagues discovered that 4E10 homes in on the hinge area and pulls out key portions of MPER buried inside the membrane. It then latches onto these newly exposed sections, forming a tighter bond with the virus, thereby blunting its ability to fuse with the cell membrane.
“The new features of MPER that we’ve discovered may be useful targets for antibody-based vaccines if they can be held in proper configuration,” said Kim. “One way of doing this would be to place them in a synthetic lipid coat on nanoparticles. If the antibodies aren’t confused by other elements of the virus’s protein envelope, this approach may elicit a strong immune response to viral presence.”
