Virion Envelope Content, Infectivity, and Neutralization Sensitivity of Simian Immunodeficiency Virus

Abstract

A truncating E767stop mutation was introduced into the envelope glycoprotein of simian immunodeficiency virus (SIV) strain SIV239-M5 (moderately sensitive to antibody-mediated neutralization and lacking five sites for N-linked carbohydrate attachment) and strain SIV316 (very sensitive to neutralization, with eight amino acid changes from the neutralization-resistant parental molecular clone, SIV239). The truncating mutation increased Env content in virions, increased infectivity, and decreased sensitivity to antibody-mediated neutralization in both strains. However, the magnitude of the effect on infectivity and neutralization sensitivity differed considerably between the two strains. In the context of strain SIV239-M5, truncation increased Env content in virions approximately 10-fold and infectivity in a reporter cell assay 24-fold. The truncated SIV239-M5 was only slightly more resistant to neutralization by polyclonal monkey sera and by monoclonal antibodies than SIV239-M5 with a full-length envelope glycoprotein. In the context of strain SIV316, truncation increased infectivity a dramatic 480-fold, while envelope content in virions was increased only about 14-fold. This dramatic increase in infectivity cannot be simply explained by the increase in envelope content and is likely due to an increase in inherent infectivity, i.e., infectivity per spike, that results from truncation. The truncated SIV316 was extremely resistant to antibody-mediated neutralization. In fact, it was not neutralized by any of the antibodies tested. When increasing amounts of SIV316 envelope glycoprotein (full length) were provided in trans to SIV316, infectivity was increased and sensitivity to neutralization was decreased, but to nowhere near the degree that was obtained when truncated SIV316 envelope glycoprotein was used. Truncated forms of SIV239 and SIV239-M5 required higher levels of soluble CD4 for inhibition of infection than their nontruncated forms; truncated SIV316 did not. Our results suggest that envelope content in SIV virions, infectivity, and resistance to antibody-mediated neutralization can be increased not only by truncation of the cytoplasmic domain but also by provision of excess envelope in trans. The striking increase in infectivity that results from truncation in the context of SIV316 appears to be due principally to an increase in inherent infectivity per spike.

4E10-Resistant Variants in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Individual with an Anti-Membrane-Proximal External Region-Neutralizing Antibody Response

“…We demonstrated that the cytoplasmic tail can modulate sensitivity to neutralization, in agreement with other studies (12,16,32,34). Furthermore, we were able to identify four amino acids in the LLP-2 domain that affect both neutralization and infectivity.…”

Dense Array of Spikes on HIV-1 Virion Particles

“…That the density of Env had a limited effect on the neutralization sensitivity of virions using diverse bnAbs was unexpected as a prior study had shown that SIV was more resistant to neutralizing antibodies with an increase in Env copy number (13). However, in that study truncations in the CTT of SIV gp41 had strong effects on infectivity and so might have altered Env conformation and/or stability.…”

“…With HIV-1, however, manipulating the CTT has either enhanced Env modestly (i.e., 3-fold) or decreased its levels (11). CTT modification also affects the antigenicity of HIV-1 Env (12) and can alter neutralization sensitivity in an Env-dependent manner (13)(14)(15)(16)(17). Stable cell line production of Env (18), and substitutions with a foreign TM domain have been shown to enhance Env on virus-like particles (VLPs); but the effects are either modest, or the reports lack details about the integrity, function, and antigenicity of trimeric Env (19)(20)(21)(22).…”

Enhanced antagonism of BST-2 by a neurovirulent SIV envelope

“…Reports suggest that truncation of gp41 cytoplasmic tail increases virion incorporation of Env, which may enhance viral replication in macrophages by increased fusion activity (24)(25)(26). Although the mutations in the present study (I805T, I828R, T829A, and V878I) did not result in truncation, they affected the cytoplasmic tail of gp41.…”