Identification and characterization of sera from HIV-infected individuals with broad cross-neutralizing activity against group M (env clade A-H) and group O primary HIV-1 isolates

Abstract

A previous study on cross-clade neutralization activity, identified three key isolates, MNlab (envB/gagB; X4 coreceptor), VI525 (envG/gagH, envA/gagA; R5X4) and CA9 (Group O; R5), that allowed discrimination of sera, likely or unlikely to neutralize primary HIV-1 isolates belonging to Group M (env clades A-H) and Group O. The prognostic ability of these three isolates was verified by means of an external validation on a different and larger set of sera. A total of 79 different sera (66 HIV-1, 10 HIV-2, 1 HIV-1+2 and 2 SIV(cpz)) were examined first for their capacity to neutralize the three key isolates, next sera were challenged against 12 other primary HIV-1 isolates of Group M (env A-H) and 2 isolates of Group O. Sera that neutralized all three isolates with an ID(50) titer of > or =1/40, also neutralized the 14 other primary isolates belonging to different genetic groups and clades. Sera that did not neutralize all three isolates did not exert broad cross-neutralizing activity. The neutralizing activity was antibody-mediated because it was absorbed and eluted from a Prot-G column. Competition-neutralization experiments using recombinant gp120 (HIV-1 MNlab) reduced the neutralizing capacity, suggesting that the neutralizing antibodies were directed against the Env protein. Remarkably, the broad cross-neutralization activity was found primarily in African female patients. In conclusion, this study confirms that three isolates are sufficient to allow identification of broad cross-neutralizing sera.

Breadth of Human Immunodeficiency Virus-Specific Neutralizing Activity in Sera: Clustering Analysis and Association with Clinical Variables

“…To date, the antibodies elicited by vaccines have had weak activity against a limited spectrum of HIV-1 strains (10,22,33). However, many HIV-infected patients make NAbs, and a small fraction make extremely potent NAbs with broad cross-reactivity (3,4,9,26,29,32). Understanding how a broadly reactive NAb response develops in some HIV-1-infected patients, and what viral epitopes are targeted, may provide important clues for vaccine design (18).…”

Identification and characterization of broadly cross-reactive neutralizing antibodies in patients infected with HIV-1 B'/C recombinant (CRF07_BC)

“…The findings from these studies indicate that the capacity of a serum to neutralize three key isolates belonging to group M (Env clades A-H) and group O predicts the ability to neutralize primary HIV-1 isolates with various genotypic and phenotypic characteristics (8). The selection of the key isolates plays a vital role in evaluating the broadly cross-reactive antibody responses that occur in HIV-1 infections.…”

“…Broad cross-neutralization of heterologous viruses may be explained by multiple responses to isolate-specific epitopes that accumulate over time or by responses against highly conserved epitopes, including those recognized by the human monoclonal antibodies 2G12, IgG1b12 and 2F5 (25). BCN antibodies in the sera of these infected patients indicate that HIV-1 strains share cross-reactive neutralization epitopes and that humans have the capacity to respond to these epitopes (8)(9)(10)(26)(27)(28).…”

“…Selection by NAb responses has been demonstrated to result in rapid and continuous in vivo evolution of viral phenotypes that are able to escape neutralization, thereby contributing to the immune response (1). However, two findings have suggested that a broadly cross-reactive neutralizing (BCN) response against HIV-1 achieves a protective role in humoral immunity: i) The discovery of broadly neutralizing monoclonal antibodies (MAbs) (2)(3)(4)(5)(6), and ii) the identification of broadly neutralizing polyclonal sera from HIV-1-infected individuals (7)(8)(9)(10). Therefore, it is likely that the production of BCN antibodies will be significant in the formulation of a protective vaccine, warranting studies of not only the homologous vaccine strain, but also intra-and interclade viral neutralization.…”

“…It has been suggested that in up to 10% of African and European HIV-infected patients, the antibody response matures and becomes cross-neutralizing. Prevention of lymphocyte infection by divergent strains has been demonstrated in in vitro peripheral blood mononuclear cell (PBMC)-neutralization assays (8,9). It has been reported that long-term nonprogressors have broader and more potent neutralization antibody titers against heterologous isolates than disease progressors (13)(14)(15)(16)(17), even though neutralizing activity against laboratory strains is observed in the two groups (14).…”