Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status

Abstract

Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4+ T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with < 5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r = − 0.9013; p < 0.0001), viral DNA (r = − 0.7696; p = 0.0005) and was associated the preservation of high CD4+ T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies.

Optimization of the EC26-2A4 Epitope in the gp41 Membrane Proximal External Region Targeted by Neutralizing Antibodies from an Elite Controller

“…For this reason, we also analyzed 71 plasma samples from the French ANRS CO15 ALT LTNP cohort comprising untreated patients 55 for the presence of antibodies against the EC26-2A4ΔM peptide alone and in conjunction with the 3S epitope in gp41, which has been previously associated with a protective effect in this cohort. 60 , 61 Interestingly, 19 of the 71 plasma samples (26.8%) showed reactivity with the EC26-2A4ΔM peptide, whereas only about 8.5% reacted in the treated cohort.…”

“…As previously reported, ALT cohort members met the following inclusion criteria: HIV seropositivity for at least 8 years and CD4 cell counts greater than 600/mm 3 for the past 5 years, whatever the viral load, but without symptoms or antiretroviral therapy. 54 , 55 The CO15 ALT cohort is funded and sponsored by ANRS and was approved by the Ethics Review Committee of Ile de France-VI (Paris, France). All LTNP patients provided written informed consent, and all methods were performed in accordance with relevant guidelines and regulations indicated by the Declaration of Helsinki.…”

Antibody-mediated control of HIV-1 infection through an alternative pathway

“…Indeed, controllers generally exhibit low or undetectable antibodies with neutralization activity, probably reflecting low antigenic stimulation of B cells. However, LTNPs in the French ALT cohort (which contains individuals with CD4 + T counts >600/L for at least 5 years and various HIV viral loads) who possessed IgG antibodies to the 3S motif of HIV-1 gp41 exerting neutralizing activity exhibited lower plasma HIV RNA and cellular HIV-1 DNA levels as well as higher CD4 + T cell counts [31] .…”

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

“…Interestingly, the presence of anti-W614A-3S bnAbs was strongly increased in untreated long-term non-progressor (LTNP) patients from the French ALT cohort (from the “Agence Nationale de Recherche sur le Sida” ANRS CO15), as compared to HIV progressor patients (25% vs. 4%), suggesting that these specific bnAbs are likely associated with a lack of disease progression. Their neutralizing capacity was inversely correlated with viral load and proviral DNA and associated with preservation of CD4 count [ 125 ]. CD4 + T cells from LTNP patients producing W614A-3S specific bnAbs could specifically recognize antigens from both HIV itself and recall antigens [ 125 ].…”

“…Their neutralizing capacity was inversely correlated with viral load and proviral DNA and associated with preservation of CD4 count [ 125 ]. CD4 + T cells from LTNP patients producing W614A-3S specific bnAbs could specifically recognize antigens from both HIV itself and recall antigens [ 125 ]. Conceivably, W614A-3S bnAbs participate in the protection of HIV-1 patients by continuous virological control resulting in maintenance of CD4 + T-cell counts and function.…”