A Signature in HIV-1 Envelope Leader Peptide Associated with Transition from Acute to Chronic Infection Impacts Envelope Processing and Infectivity

Abstract

Mucosal transmission of the human immunodeficiency virus (HIV) results in a bottleneck in viral genetic diversity. Gnanakaran and colleagues used a computational strategy to identify signature amino acids at particular positions in Envelope that were associated either with transmitted sequences sampled very early in infection, or sequences sampled during chronic infection. Among the strongest signatures observed was an enrichment for the stable presence of histidine at position 12 at transmission and in early infection, and a recurrent loss of histidine at position 12 in chronic infection. This amino acid lies within the leader peptide of Envelope, a region of the protein that has been shown to influence envelope glycoprotein expression and virion infectivity. We show a strong association between a positively charged amino acid like histidine at position 12 in transmitted/founder viruses with more efficient trafficking of the nascent envelope polypeptide to the endoplasmic reticulum and higher steady-state glycoprotein expression compared to viruses that have a non-basic position 12 residue, a substitution that was enriched among viruses sampled from chronically infected individuals. When expressed in the context of other viral proteins, transmitted envelopes with a basic amino acid position 12 were incorporated at higher density into the virus and exhibited higher infectious titers than did non-signature envelopes. These results support the potential utility of using a computational approach to examine large viral sequence data sets for functional signatures and indicate the importance of Envelope expression levels for efficient HIV transmission.

Neutralizing Antibody Escape during HIV-1 Mother-to-Child Transmission Involves Conformational Masking of Distal Epitopes in Envelope

“…Alternatively, increased Env content may enhance neutralization through increased avidity (26,42). Moreover, recent studies have reported that increased Env content may be a signature of transmitted variants (3,16). However, for the 2 variants transmitted to the infants examined here, neutralization resistance to maternal plasma did not appear to be explained by differences in Env content relative to maternal variants.…”

Impact of Clade, Geography, and Age of the Epidemic on HIV-1 Neutralization by Antibodies

“…A manifestation of this may be the shorter hypervariable loop lengths that tend to be selected at transmission (99)(100)(101), which in turn may better expose key neutralization epitopes. Also, selection of mutations associated with increased Env expression levels might enhance both infectivity and neutralization sensitivity (102)(103)(104). Chronic viruses, on the other hand, might acquire general features associated with neutralization resistance under continuous selection by autologous immune responses.…”

Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1

“…T/F Envs tend to have shorter variable loops and/or fewer N-linked glycosylation sites; this pattern is clearly evident in clades A, C, and D (24-26) but marginal in clade B (24,27,28). Protein sequence signatures have been identified that are associated with T/F viruses (27); these signatures may be associated with Env expression levels (29). A critical question for HIV-1 vaccine development is to determine whether T/F HIV-1 Envs differ from chronic and consensus Envs in their ability to induce antibody responses.…”