Antibody response against selected epitopes in the HIV-1 envelope gp41 ectodomain contributes to reduce viral burden in HIV-1 infected patients

Abstract

The ectodomain of gp41 is the target of potent binding and neutralizing antibodies (NAbs) and is being explored in new strategies for antibody-based HIV vaccines. Previous studies have suggested that the W164A-3S (3S) and EC26-2A4 (EC26) peptides located in the gp41 ectodomain may be potential HIV vaccine candidates. We assessed 3S- and EC26-specific binding antibody responses and related neutralizing activity in a large panel of chronic HIV-1-infected Portuguese individuals on ART. A similar proportion of participants had antibodies binding to 3S (9.6%) and EC26 (9.9%) peptides but the level of reactivity against 3S was significantly higher compared to EC26, except in the rare patients with double peptide reactivity. The higher antigenicity of 3S was unrelated with disease stage, as assessed by CD4+ T cell counts, but it was directly related with plasma viral load. Most patients that were tested (89.9%, N = 268) showed tier 1 neutralizing activity, the potency being inversely associated with plasma viral load. In the subset of patients that were tested for neutralization of tier 2 isolates, neutralization breadth was inversely correlated with plasma viral load and directly correlated with CD4+ T cell counts. These results are consistent with a role for neutralizing antibodies in controlling viral replication and preventing the decline of CD4+ T lymphocytes. Importantly, in patients with 3S-specific antibodies, neutralizing titers were inversely correlated with viral RNA levels and proviral DNA levels. Moreover, patients with 3S and/or EC26-specific antibodies showed a 1.9-fold higher tier 2 neutralization score than patients without antibodies suggesting that 3S and/or EC26-specific antibodies contribute to neutralization breadth and potency in HIV-1 infected patients. Overall, these results suggest that antibodies targeting the S3 and EC26 epitopes may contribute to reduce viral burden and provide further support for the inclusion of 3S and EC26 epitopes in HIV-1 vaccine candidates.

The Association of HIV-1 Neutralization in Aviremic Children and Adults with Time to ART Initiation and CD4+/CD8+ Ratios

“…Neutralization percentages of each purified IgG at a concentration of 0.2 μg/mL against each of the viruses are shown in Figure 2 a. To assess neutralization breadth and potency, we used a previously described scoring system based on the percentage of inhibition of each virus of the panel using a single plasma IgG concentration (0.2 µg/mL) [ 24 , 25 ]. In this cohort, the median neutralization score was 1.0 ± 1.8, ranging from 0 to 8.…”

“…No significant neutralization of the VSV-pseudotyped control was observed in any of the purified IgGs analyzed. a A cumulative score was computed for each plasma, taking into account the neutralization scores against all six viruses using a previously described scoring system based on the percentage of inhibition of each virus of the panel using a single plasma IgG concentration (0.2 µg/mL) [25,26]. Thresholds for cumulative scores were determined to categorize plasma as elite, broad, cross, or weak/no neutralization.…”

Dichotomy in Neutralizing Antibody Induction to Peptide-Conjugated Vaccine in Squalene Emulsion Contrast With Aluminum Hydroxide Formulation

“…Animal models including mice, rabbits, and macaques showed immunogenicity of the W614A-3S peptide when coupled with carrier protein and adjuvanted in incomplete Freund adjuvant (IFA), a water-in-oil emulsion ( 9 ). Importantly, natural Abs against W614A-3S eluted from the plasma of HIV-1 patients showed neutralizing activity and were detected exclusively in patients with high CD4 counts and undetectable (<20 copies/ml) or controlled viral loads ( 9 , 10 ). W614A-3S Abs were detected in 23.5% (16/68) of untreated long-term non-progressor (LTNP) patients compared with <5% of HIV-1 progressor patients.…”

Multi-trial analysis of HIV-1 envelope gp41-reactive antibodies among global recipients of candidate HIV-1 vaccines

“…However, more recently it was observed that the rate of increase in the combined anti-gp41 IgM and IgG antibody concentration was strongly correlated with the initial rate of HIV-1 infectivity decay, suggesting a role of anti-gp41 antibody early in natural infection ( 5 ). In the context of chronic HIV infection, neutralizing anti-gp41 antibodies may develop ( 6 , 7 ) and gp41 may also be an effective target for antibody-dependent cellular cytotoxicity ( 8 ).…”