Evolution of antibody landscape and viral envelope escape in an HIV-1 CRF02_AG infected patient with 4E10-like antibodies

Abstract

BackgroundA minority of HIV-1 infected individuals develop broad cross-neutralizing (BCN) plasma antibodies that are capable of neutralizing a spectrum of virus variants belonging to different HIV-1 clades. The aim of this study was to identify the targeted epitopes of an individual with BCN plasma antibodies, referred to as ITM4, using peptide phage display. This study also aimed to use the selected mimotopes as tools to unravel the evolution of the antibody landscape and the viral envelope escape which may provide us with new insights for vaccine design.ResultsThis study led us to identify ITM4 plasma antibodies directed to the 4E10 epitope located in the gp41 membrane-proximal external region (MPER). Analysis of antibody specificities revealed unusual immunogenic properties of the ITM4 viral envelope, as not only the V3 loop and the gp41 MPER but also the C1 and lentivirus lytic peptide 2 (LLP2) region seem to be targets of the immune system. The 4E10-like antibodies are consistently elicited during the 6-year follow up period. HIV-1 ITM4 pseudoviruses showed an increasing resistance over time to MPER monoclonal antibodies 4E10 and 2F5, although no changes are found in the critical positions of the epitope. Neutralization of COT6.15 (subtype C; 4E10-sensitive) pseudoviruses with alanine substitutions in the MPER region indicated an overlapping specificity of the 4E10 monoclonal antibody and the ITM4 follow up plasma. Moreover the 4E10-like antibodies of ITM4 contribute to the BCN capacity of the plasma.ConclusionsUsing ITM4 BCN plasma and peptide phage display technology, we have identified a patient with 4E10-like BCN antibodies. Our results indicate that the elicited 4E10-like antibodies play a role in virus neutralization. The viral RNA was isolated at different time points and the ITM4 envelope sequence analysis of both early (4E10-sensitive) and late (4E10-resistant) viruses suggest that other regions in the envelope, outside the MPER region, contribute to the accessibility and sensitivity of the 4E10 epitope. Including ITM4 specific HIV-1 Env properties in vaccine strategies may be a promising approach.

The Genetic Bottleneck in Vertical Transmission of Subtype C HIV-1 Is Not Driven by Selection of Especially Neutralization-Resistant Virus from the Maternal Viral Population

“…Longer loop length was associated with greater resistance to neutralization by the monoclonal antibody 4E10 over the whole V1-V5 region (P ϭ 0.006 [data not shown]), though with only R 2 ϭ 0.11. gp41 was not sequenced; thus, we could not examine potential linked changes in the 4E10 epitope, although other regions or structures can impact epitope recognition (13).…”

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference

“…A range of viruses from patients at various stages of disease progression were studied for susceptibility to neutralisation, using autologous sera or monoclonal antibodies. All viruses were shown to escape from the neutralising antibody response mounted by the host [ 21 - 23 ]. Interestingly, viruses with escape mutations were still susceptible to neutralization with autologous sera obtained at later time points or with certain monoclonal antibodies.…”

Expression and immunological characterization of cardamom mosaic virus coat protein displaying HIV gp41 epitopes

“…Neutralizing antibodies reacting with the 2F5 epitope are reportedly responsible for serum neutralizing activity . The presence of 4E10‐like antibodies in the broadly cross neutralizing plasma of an HIV positive person and their importance in virus neutralization have been reported . These studies show the presence of antibodies to these epitopes in some, but not all, HIV infected persons, explaining the reactivity of the chimeric proteins with sera from HIV infected persons.…”

“…However not all sera recognized the chimeric proteins, because these antibodies are not produced in all such patients. Several studies assessing the presence of such antibodies in the sera of HIV patients have shown that antibodies specific to Kennedy peptide, 2F5 and 4E10 epitopes are not uniformly present in persons infected with HIV (33)(34)(35)(36)(37)(38).…”