Longitudinal Analysis of Early HIV-1-Specific Neutralizing Activity in an Elite Neutralizer and in Five Patients Who Developed Cross-Reactive Neutralizing Activity

Abstract

We previously established that at 3 years postseroconversion, ϳ30% of HIV-infected individuals have cross-reactive neutralizing activity (CrNA) in their sera. Here we studied the kinetics with which CrNA develops and how these relate to the development of autologous neutralizing activity as well as viral escape and diversification. For this purpose, sera from five individuals with CrNA and one elite neutralizer that were obtained at three monthly intervals in the first year after seroconversion and at multiple intervals over the disease course were tested for neutralizing activity against an established multiclade panel of six viruses. The same serum samples, as well as sera from three individuals who lacked CrNA, were tested for their neutralizing activities against autologous clonal HIV-1 variants from multiple time points covering the disease course from seroconversion onward. The elite neutralizer already had CrNA at 9.8 months postseroconversion, in contrast with the findings for the other five patients, in whom CrNA was first detected at 20 to 35 months postseroconversion and peaked around 35 months postseroconversion. In all patients, CrNA coincided with neutralizing activity against autologous viruses that were isolated <12 months postseroconversion, while viruses from later time points had already escaped autologous neutralizing activity. Also, the peak in gp160 sequence diversity coincided with the peak of CrNA titers. Individuals who lacked CrNA had lower peak autologous neutralizing titers, viral escape, and sequence diversity than individuals with CrNA. A better understanding of the underlying factors that determine the presence of CrNA or even an elite neutralizer phenotype may aid in the design of an HIV-1 vaccine.

Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

“…Therefore, the development or maintenance of these MAbs after VRC01 in donor 45 was (11) 3 (33) 1 (11) 6 (67) specific to the relevant autologous viruses but not necessarily associated with better neutralization breadth of "irrelevant" heterologous viruses circulating globally. This highlights the complexity of underlying factors that influence the broadening of antibody neutralization (16,23). Although most of the donor 45 Env variants from 2001 plasma was neutralized by VRC03, VRC06, and VRC06b, Env variants from 2006 plasma were resistant, suggesting that the virus was able to escape these newly developed antibody variants.…”

Most rhesus macaques infected with the CCR5-tropic SHIV AD8 generate cross-reactive antibodies that neutralize multiple HIV-1 strains

“…Although the emergence of broadly reacting anti-HIV-1 NAbs in elite neutralizers has been associated with multiple rounds of somatic hypermutation (7), little is known about vaccine strategies able to elicit such antibodies. Longitudinal studies of HIV-1-infected persons have suggested that set-point plasma virus loads, CD4 + T-cell levels, duration of the infection, or antibody-binding avidity may contribute to the development of cross-reacting NAbs (5,8,9). It is also possible that the induction of such antibodies depends on unique gp120 epitopes associated with specific HIV-1 strains and individual B-cell repertoires or is simply a random process (10,11).…”

Les anticorps anti-VIH-1 et la transmission virale de cellule à cellule

“…Il est intéressant de noter que les bNAb actifs chez l'animal sont ceux qui sont capables de bloquer la propagation virale de cellule à cellule en culture [7]. Les anticorps monoclonaux sont utilisés chez l'homme pour le traitement de nombreuses pathologies tumorales, inflammatoires ou auto-immunes 1 …”

“…Alors qu'ils étaient considérés comme des exceptions il y a quelques années, ces individus représenteraient jusqu'à 10 à 20 % des personnes infectées. Malheureusement pour ces patients, la pré-sence de bNAb n'est pas corrélée avec une évolution favorable de la maladie en absence de traitement antirétroviral, des virus résistants à la réponse humorale apparaissant continuellement [1]. Jusqu'à récemment, les anticorps neutralisants clonés à partir de lymphocytes B humains disponibles étaient souvent peu actifs ou peu cross-réactifs.…”