Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Abstract

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibodydependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_ AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

“…To exclude any possible impact of this technical aspect of IMCs with LucR on our ADCC results, full length IMCs (n=7) that do not contain a report gene were used to evaluate ADCC of the affinity matured RV305 C1C2-specific antibodies DH677.3 and DH677.4 and A32 [2], against target cells positive for intracellular p24 (p24+) and with downregulated CD4 (CD4-). As clade CRF01_AE possess a histidine at Env HXB2 position 375 that influences sensitivity to CD4i antibody binding and ADCC [16, 17] only clade B and clade C isolates were used.…”

HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites

“…Overall, our data concur with findings of Zoubchenok et al except for the lower prevalence of His at position 105 which is likely a bias caused by small sample size. In another study, Prevost et al showed that AE subtype expose the ADCC epitopes on the Env glycoprotein as a consequence of the H375 substitution (Prevost et al, 2017). Furthermore, the insensitivity of AE subtype to broadly neutralizing antibodies that bind the CD4 interacting region on Env has been well documented (Chen et al, 2016; Utachee et al, 2014).…”

Exposing HIV-1 Env: Implications for therapeutic strategies

“…Most HIV-1 group M Envs have an empty Phe 43 cavity due to the presence of a small residue such as serine at position 375 (S375), which favors a closed Env conformation [13,14]; however, CRF01_AE isolates have a naturally occurring histidine (H375) at this position [15]. The substitution of S375 with bulky hydrophobic residues fills the Phe 43 cavity and predisposes Env to adopt more "open" conformations [13,15,16]. Accordingly, histidine or tryptophan substitutions at this position (S375H or S375W) increase the susceptibility of cells infected with HIV-1 clade B (or other clades) to ADCC mediated by CD4i antibodies such as the cluster A antibody A32 ( Figure 1B) [16].…”