Kinetics of protective antibodies are determined by the viral surface antigen

Abstract

Delayed and weak virus neutralizing antibody (nAb) responses represent a hallmark correlating not only with the establishment of persistent infection but also with unsuccessful vaccine development. Using a reverse genetic approach, we evaluated possible underlying mechanisms in 2 widely studied viral infection models. Swapping the glycoproteins (GPs) of lymphocytic choriomeningitis virus (LCMV, naturally persisting, noncytolytic, inefficient nAb inducer) and vesicular stomatitis virus (VSV, nonpersisting, cytolytic, potent nAb inducer) transferred the only target of nAb's from either virus to the other. We analyzed the nAb response to each of the 2 recombinant and parent viruses in infected mice and found that nAb kinetics were solely determined by the viral surface GP and not by the virus backbone. Moreover, the slowly and poorly nAb-triggering LCMV virion was a potent immunogenic matrix for the more antigenic VSV-GP. These findings indicate that the viral GP determines nAb kinetics largely independently of the specific viral infection context. They further suggest that structural features of viral GPs or coevolutionary adaptation of the virus's GP to the host's naive B cell repertoire, or both, may critically limit nAb kinetics and improvement of vaccine efficacy.

Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors

“…A chimeric VSV using LCMV-G had been shown to replicate to high titer (11), and one study suggested that virions of a related virus (Lassa virus) are released from the apical surface of infected epithelial cells (31), although another study showed basolateral release of LCMV from airway epithelia (32). Infection of the brain after injection into the eye of VSV(LCMV-G) first led to labeled retinorecipient areas and then several secondary locations in the visual pathway.…”

“…VSV is lethal to individual cells, and to an animal when injected into the brain, but it is significantly less toxic after natural infections in humans and is being developed as a vaccine vector for humans (9). In addition, VSV has demonstrated great versatility in its ability to be pseudotyped with other virus' glycoproteins (10)(11)(12)(13), and its genome has been successfully engineered by using straightforward manipulations (14).…”

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

“…Several factors contribute to the inefficient induction of neutralizing Abs such as low immunogenicity of viral structures (10), low precursor frequency of virus-specific B cells (11), and induction of T cell-driven immune pathology (9,12,13). CD4 T cells induce polyclonal B cell activation and hypergammaglobulinemia in chronic LCMV infection at the cost of the effective generation of neutralizing Abs (12).…”

Judging a virus by its cover

“…Does this response occur during infection of other host species with viruses other than LCMV and VSV, or does the study of Pinschewer et al (10) merely illustrate a curious exception? Some of the other viruses known to induce early neutralizing antibody responses, such as influenza and polio, induce early, protective IgM responses.…”