Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1

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Abstract
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. A fraction of those infected with HIV develop broadly neutralizing antibodies (bNAbs) capable of preventing cell-infection by diverse HIV isolates; the type of antibodies we wish to elicit by vaccination. Identifying factors associated with the natural development of bNabs, and defining the timing of their emergence and their epitope specificities, will assist the development of more effective immunogens and vaccination protocols. Here we performed a neutralization screen of plasma samples collected longitudinally from HIV-1-infected subjects and determined that on average, cross-neutralizing antibody responses emerge 2–3 years, but as early as one year, following infection. A significant portion of the earliest cross-neutralizing antibody response to HIV targets epitopes that are present on the virion-associated trimeric Env spike, but not the corresponding soluble monomeric versions of that viral protein. Our study highlights the importance of eliciting by vaccination antibodies with this type of complex epitope specificities.