HIV gp41

HIV gp41 Full Name

human immunodeficiency virus glycoprotein 41

HIV gp41 Introduction

HIV-1 gp41 is the transmembrane subunit of the envelope glycoprotein (Env) complex, pairing with gp120 to form a trimer of heterodimers that mediates viral entry. The gp41 ectodomain contains several conserved functional regions, including the fusion peptide (FP), N-terminal heptad repeat (HR1/NHR), C-terminal heptad repeat (HR2/CHR), the membrane-proximal external region (MPER), the loop/disulfide-bonded region, and the cytoplasmic tail (CT). During entry, gp120 engagement with CD4 triggers conformational changes that expose gp41 HR1 and HR2, which then assemble into a six-helix bundle to bring viral and cellular membranes into close proximity, enabling fusion pore formation and lipid mixing. The FP, HR1/HR2, MPER, and loop regions collectively govern the kinetics, efficiency, and stability of fusion, forming the mechanistic core that drives the transition from prefusion intermediates to a postfusion hairpin. gp41's conserved architecture underlies susceptibility to fusion inhibitors and the development of therapeutic peptides targeting HR1-HR2 interactions.

The gp41 cytoplasmic tail (CT) is unusually long and serves regulatory roles, including modulating Env incorporation into virions, surface expression, fusogenic potential, and ectodomain conformation. Truncation or mutation of the CT alters Env trafficking, gp120 shedding, and pre- versus post-fusion dynamics, reflecting allosteric effects on antibody recognition and neutralization sensitivity. The loop/disulfide-bonded region of gp41 forms a key interface for gp120–gp41 association, linking receptor-induced conformational changes in gp120 to activation of the gp41 fusion machinery. Mutational analyses demonstrate that disruption of this interface can prevent fusion without compromising overall gp41 folding, highlighting the interdependence of structural regions. Variability across isolates, shaped by host selective pressures, influences the plasticity of gp120–gp41 interactions and contributes to strain-specific differences in fusion efficiency and antibody accessibility.

gp41 represents a central target for HIV therapeutics and vaccine design. The six-helix bundle formed by HR1 and HR2 underpins the mechanism of fusion inhibitors, such as CHR-derived peptides (C34) and T20 (enfuvirtide), which stabilize nonproductive intermediates and prevent proper bundle formation. Small molecules and lectins have also been developed to interfere with HR1-HR2 interactions or block gp41 conformational changes, providing alternative strategies to peptide inhibitors. Conserved regions such as the MPER are key targets for broadly neutralizing antibodies (bnAbs), though their conformational accessibility and exposure during infection are nuanced, influencing immunogen design. Vaccine strategies focus on stabilizing prefusion Env trimers to present functional gp41 epitopes while minimizing misdirected responses to postfusion conformations or shed fragments. Integrating structural, biochemical, and virological insights highlights gp41 as a multifunctional hub that drives viral entry, regulates Env dynamics, and serves as a foundation for next-generation fusion inhibitors and rational vaccine development.

Alternate Names for HIV gp41

env; Glycoprotein 41; gp41; TM; Transmembrane protein; HIV gp41 L

• Humanized Control Antibodies for Infectious Disease Diagnostics
• Humanized Control Antibodies for Infectious Disease Diagnostics
• Humanized Control Antibodies for Infectious Disease Diagnostics
• Humanized Control Antibodies for Infectious Disease Diagnostics

• 1. Blumenthal R., et al. HIV Entry and Envelope Glycoprotein-mediated Fusion. Journal of Biological Chemistry. 2012;287(49):40841-40849.
  2. Pancera M., et al. Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Nature. 2014;514(7523):455-461.
  3. Teixeira C., et al. Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug. European Journal of Medicinal Chemistry. 2011;46(4):979-992.