Characteristics of the earliest cross-neutralizing antibody response to HIV-1.
Bottom Line: Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%-30% of HIV-1+ subjects.The timing of the initial development of such anti-viral responses is unknown.Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols.
Affiliation: Seattle BioMed, Seattle, Washington, USA.
Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%-30% of HIV-1+ subjects. The timing of the initial development of such anti-viral responses is unknown. It is also unknown whether the emergence of these responses coincides with the appearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein (Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soon after and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibody responses first become evident on average at 2.5 years and, in rare cases, as early as 1 year following infection. If cross-neutralizing antibody responses do not develop during the first 2-3 years of infection, they most likely will not do so subsequently. Our results indicate a potential link between the development of cross-neutralizing antibody responses and specific activation markers on T cells, and with plasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Env regions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on the virion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects that did not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other than the CD4-BS. Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols. Since antibodies to complex epitopes that are present on the virion-associated envelope spike appear to be key components of earliest cross-neutralizing activities of HIV-1+ plasmas, then emphasis should be made to elicit similar antibodies by vaccination.
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Mentions: Potentially, the above results suggested that the earliest cross-neutralizing activities in HIV-1+ plasmas are primarily targeting the extracellular gp120 subunit. To address this point, we depleted the anti-gp120 antibodies from six plasmas (AC049, AC053, AC071, AC128, AC131, AC180) displaying cross-neutralizing activities, and three of the plasmas (AC098, AC115, AC212), which only neutralized SF162 (Figure S1). Although during these depletion experiments we used gp120 from one clade B virus (SF162), we verified that this treatment eliminated anti-gp120 antibodies against other gp120s, from both clade B and clade C viruses (Figure S1). Then, the neutralizing activities of non-depleted and of the corresponding gp120-antibody-depleted plasmas were compared against several clade B and C viruses (the data are summarized in Figure 5A and representative examples are shown in Figure 6). Removal of the anti-gp120 antibodies from plasmas with narrow breadth resulted in complete loss in neutralizing activity. In contrast, removal of the anti-gp120 antibodies from plasmas with breadth had a diverse effect on the neutralizing activities of plasmas, depending on the plasma / targeted virus pairing. In most cases examined, either no changes in IC50 titers were recorded or changes smaller than 0.5Log10 in IC50 were recorded. However, in specific cases the neutralizing activity of given plasma against a given virus was completely lost when the anti-gp120 antibodies were removed. That was the case of plasma AC131 and the QH0692 and SF162 viruses (but not other viruses tested); or the case of plasma AC053 and the YU2, REJO and Du422 viruses (but that was not the case for this plasma's anti-TRO.11, -CAAN or -ZM214 neutralizing activities).