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: To define the earliest period following HIV-1 infection when cross-neutralizing antibody responses appear in plasma we determined the neutralizing activities of plasmas collected within a few months and up to several years post HIV-1 infection from anti-retroviral naïve subjects infected with clade B viruses, against 20 heterologous clade A, B and C primary isolates (Figures 1 and 2). Plasma samples from two independent cohorts were examined. The samples from the Vanderbilt cohort (VC) were, for the most part, collected within the first year of infection (Figure 1). The breadth of cross-neutralizing activity (i.e., the percentage of viruses neutralized by any given plasma out of the total number of viruses the plasma was tested against) was minimal (less than 50%), in agreement with previous observations , . In most cases, these ‘early’ plasmas efficiently neutralized the ‘easy-to-neutralize’ primary SF162.LS virus, but not other primary viruses examined here. In the few cases where neutralizing activity against viruses other than SF162 was observed, the potency of neutralization was for the most part very weak and the neutralizing activities targeted clade B viruses. In two cases (subjects VC20017 and VC20027) the ‘early’ plasmas also neutralized a few non-clade B viruses. Plasma VC20027 collected within the first year of infection neutralized 6/9 clade B, 3/6 clade C and 1/4 clade A viruses. Plasma sample collected from subject VC20017 during the first year of infection neutralized 4/9 clade B viruses, the clade A virus Q259d2.17, and the clade C viruses ZM214M and Du422.1. These observations indicate that cross-neutralizing antibody responses begin to emerge during the first year of HIV-1 infection, but that such responses are weak in potency and narrow in breadth; rarely targeting viruses from clades other than the one the patient is infected with.