Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections

Abstract

Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design

“…Several previous studies have observed that the transmitted virus is underglycosylated in an HIV-1 subtype C cohort (4) and in an HIV-1 subtype A cohort (19), although this effect was less apparent overall in a subtype B cohort (19,21,22), with the exception of underrepresentation of a glycosylation site at position 413 (24). We have been able to confirm this observation of reduced glycosylation of the transmitted virus in this large subtype C cohort (Fig.…”

“…In several studies, there has been consistent observation of reduced length of the variable regions in the Env protein and/or reduced N-linked glycosylation density of the Env protein, features reported for subtypes C, A, and D HIV-1 (4,19,20) but less clear for subtype B HIV-1 (19,21,22). An analysis of a large data set of subtype B env sequences revealed in the transmitted viruses selection for a basic amino acid at position 12 in the Env leader sequence that increases Env density on virions and underrepresentation of a glycosylation site at codon 413 (23,24), although this site is typically not present in subtype C HIV-1. It has been reported that the reduced glycosylation of the Env protein of transmitted viruses enhances binding to ␣4␤7 integrin associated with CD4 ϩ T cells found in gut-associated lymphoid tissue and impacts Env conformation and the interaction with CD4 (25), although this relationship was not detected in a larger sampling of transmitted viruses (13).…”

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…In this context, it is critical to know whether transmitted viruses possess unique biological properties that predispose them to establish new infections more efficiently. This is a controversial topic, because some studies have reported TF-specific traits (22,24,26,52,(55)(56)(57), whereas others have failed to confirm these results (27,28,53,58,59). Some of these discrepancies are likely due to the fact that most previous analyses did not compare HIV-1 strains from transmission pairs.…”

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

“…Despite this, within-host HIV-1 evolution in response to antiretroviral (61,72), host cellular immune (15,50,71,94,95), antibody (46), and vaccine-induced (103) selection pressures occurs along generally predictable mutational pathways (3,84). Studying these evolutionary pathways can offer insight into the immunopathogenesis of HIV-1 and may help inform the design of immune-based interventions and vaccines.…”