Abstract
The envelope glycoproteins (Envs) of HIV-1 are embedded in the cholesterol-rich lipid membrane of the virus. Chemical depletion of cholesterol from HIV-1 particles inactivates their infectivity. We observed that diverse HIV-1 strains exhibit a range of sensitivities to such treatment. Differences in sensitivity to cholesterol depletion could not be explained by variation in Env components known to interact with cholesterol, including the cholesterol-recognition motif and cytoplasmic tail of gp41. Using antibody-binding assays, measurements of virus infectivity, and analyses of lipid membrane order, we found that depletion of cholesterol from HIV-1 particles decreases the conformational stability of Env. It enhances exposure of partially cryptic epitopes on the trimer and increases sensitivity to structure-perturbing treatments such as antibodies and cold denaturation. Substitutions in the cholesterol-interacting motif of gp41 induced similar effects as depletion of cholesterol. Surface-acting agents, which are incorporated into the virus lipid membrane, caused similar effects as disruption of the Env-cholesterol interaction. Furthermore, substitutions in gp120 that increased structural stability of Env (i.e. induced a "closed" conformation of the trimer) increased virus resistance to cholesterol depletion and to the surface-acting agents. Collectively, these results indicate a critical contribution of the viral membrane to the stability of the Env trimer and to neutralization resistance against antibodies. Our findings suggest that the potency of poorly neutralizing antibodies, which are commonly elicited in vaccinated individuals, may be markedly enhanced by altering the lipid composition of the viral membrane.
Highlights
The envelope glycoproteins (Envs) of HIV-1 are embedded in the cholesterol-rich lipid membrane of the virus
Using antibody-binding assays, measurements of virus infectivity, and analyses of lipid membrane order, we found that depletion of cholesterol from HIV-1 particles decreases the conformational stability of Env
We examined the effects of methyl-by treatment with -cyclodextrins (BCDs) (MBCD) on diverse HIV-1 strains and observed a wide range of sensitivities that could not be explained by differences in known membraneinteracting domains of Env
Summary
Envelope glycoprotein; Ab, antibody; MPER, membrane-proximal ectodomain region; CT, cytoplasmic tail; BCD, -cyclodextrin; MBCD, methyl--cyclodextrin; GML, glycerol monolaurate; N-9, nonoxynol-9; VSV-G, G protein of vesicular stomatitis virus; CoR-BS, coreceptor-binding site; CD4-BS, CD4-binding site; HOS, human osteosarcoma; GP, generalized polarization; DMEM, Dulbecco’s modified Eagle’s medium; HRP, horseradish peroxidase. Some reports suggest that depletion of cholesterol physically disrupts the virion membrane [40, 44], whereas others failed to note effects on virus morphology or protein composition [42, 48]. We examined the effects of methyl-BCD (MBCD) on diverse HIV-1 strains and observed a wide range of sensitivities that could not be explained by differences in known membraneinteracting domains of Env. Using a panel of primary isolates and closely matched variants, we observed that sensitivity of Envs to cholesterol depletion corresponds with their inherent conformational stability. The surface-acting agent nonoxynol-9 induced similar effects on Env stability and increased HIV-1 sensitivity to neutralization by otherwise low-potency Abs that target gp120 and gp
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