Abstract
Our central hypothesis is that protection against HIV infection will be powerfully influenced by the magnitude and quality of the B cell response. Although sterilizing immunity, mediated by pre-formed abundant and potent antibodies is the ultimate goal for B cell-targeted HIV vaccine strategies, scenarios that fall short of this may still confer beneficial defenses against viremia and disease progression. We evaluated the impact of sub-sterilizing pre-existing neutralizing antibody on the B cell response to SHIV infection. Adult male rhesus macaques received passive transfer of a sub-sterilizing amount of polyclonal neutralizing immunoglobulin (Ig) purified from previously infected animals (SHIVIG) or control Ig prior to intra-rectal challenge with SHIVSF162P4 and extensive longitudinal sampling was performed. SHIVIG treated animals exhibited significantly reduced viral load and increased de novo Env-specific plasma antibody. Dysregulation of the B cell profile was grossly apparent soon after infection in untreated animals; exemplified by a ≈50% decrease in total B cells in the blood evident 2–3 weeks post-infection which was not apparent in SHIVIG treated animals. IgD+CD5+CD21+ B cells phenotypically similar to marginal zone-like B cells were highly sensitive to SHIV infection, becoming significantly decreased as early as 3 days post-infection in control animals, while being maintained in SHIVIG treated animals, and were highly correlated with the induction of Env-specific plasma antibody. These results suggest that B cell dysregulation during the early stages of infection likely contributes to suboptimal Env-specific B cell and antibody responses, and strategies that limit this dysregulation may enhance the host’s ability to eliminate HIV.
Highlights
One of the goals of vaccination is to establish B cell memory that can be efficiently recruited upon virus exposure to develop antibodies that are directed at conserved epitopes in order to prevent or control infection, and this goal has been a substantial hurdle for the human immunodeficiency type 1 (HIV-1) vaccine field
Male rhesus macaques received normal IgG (n = 5) or IgG isolated from SHIVSF162P4 infected animals (n = 5) that had developed neutralizing antibodies, and which was delivered at a substerilizing dose, and are referred to as Normal IgG (NIgG) and SHIVIG
We identified a specific B-cell population (MZ-like) that is highly and affected during acute simian-human immunodeficiency virus (SHIV) infection, and we identified a direct association with the preservation of this B cell subset and the production of endogenous Env-specific binding antibodies
Summary
One of the goals of vaccination is to establish B cell memory that can be efficiently recruited upon virus exposure to develop antibodies that are directed at conserved epitopes in order to prevent or control infection, and this goal has been a substantial hurdle for the human immunodeficiency type 1 (HIV-1) vaccine field. Transferred human polyclonal or monoclonal NAbs (NmAbs) have been widely used to test for protection against infection in nonhuman primates (NHP) in simian-human immunodeficiency virus (SHIV) models of HIV-1 infection. In those settings, passive administration of NmAbs was able to fully protect against intravenous [3] or mucosal [4,5,6,7,8,9] SHIV challenge. A confirmatory study later reported similar findings using preexposure with NmAb [14], and both studies are exemplary in the demonstration of the dual functionality of antibodies in the setting of HIV-1 infection, as the killing of infected cells was likely accomplished by Fc-mediated effector functions
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