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.
Highlights
Despite recent progress in reducing the number of new infections, 1.7 million [1.2 million–2.2 million] people became newly infected with HIV in 2019 and HIV/AIDS is still among the leading causes of disease burden and mortality in sub-Saharan A frica[1]
Despite numerous attempts using different strategies, broadly neutralizing monoclonal antibodies (bnAbs) against membrane proximal external-region (MPER) have been difficult to elicit in animal models and the few vaccines developed based on MPER epitopes elicited only neutralizing antibodies of low potency and limited b readth[5,13,14,15]
Figure 1. 3S and EC26-specific antibody frequency and reactivity in plasma from HIV-1-infected Portuguese. (A) Peptide-specific antibody reactivity levels in all patients; (B) Proportion of HIV-1 plasma samples reacting with the peptides in viraemic and aviraemic patients; C and D) Antibody frequency according to HIV RNA and CD4+ T cells counts; (E) Plasma reactivity levels against both peptides in viraemic and aviraemic patients
Summary
Despite recent progress in reducing the number of new infections, 1.7 million [1.2 million–2.2 million] people became newly infected with HIV in 2019 and HIV/AIDS is still among the leading causes of disease burden and mortality in sub-Saharan A frica[1]. Many different broadly neutralizing monoclonal antibodies (bnAbs) targeting epitopes in gp[120] or gp[41] have been isolated from HIV controllers and elite n eutralizers[5]. These bnAbs allowed the identification of key vulnerable sites on the HIV-1 envelope glycoprotein (gp120/gp41) and are guiding the design of the new generation of HIV vaccines[6]. Despite numerous attempts using different strategies, bnAbs against MPER have been difficult to elicit in animal models and the few vaccines developed based on MPER epitopes elicited only neutralizing antibodies of low potency and limited b readth[5,13,14,15]. EC26 peptide conjugates and a optimized version of the peptide named EC26-2A4-ΔM elicited the prodution of antibodies that neutralized tier 1 HIV-1 strains and in the case of EC262A4ΔM did not react with cardiolipin and p hospholipids[19,20,21]
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