Class Switch Recombination and Somatic Hypermutation of Virus-Neutralizing Antibodies Are Not Essential for Control of Friend Retrovirus Infection

Abstract

Susceptibilities to retroviral infections differ within a single host species as exemplified by the presence of slow or rapid progressors and elite controllers among individuals infected with human immunodeficiency virus (1). Friend virus (FV) infection of adult immunocompetent mice is useful to study the genetic, molecular, and cellular bases of resistance against retroviruses (2, 3). FV consists of replication-competent Friend murine leukemia virus (FMuLV) and defective spleen focus-forming virus (SFFV). In C57BL/6 (B6) mice homozygously possessing the resistant Fv2 allele (4), not only is SFFV-induced proliferation of infected erythroid progenitor cells limited, but they are also actively eliminated by cellular immune responses (5). CD4 ϩ T cells are required for SFFV elimination, while B-lymphocytes are required for F-MuLV elimination (5, 6). FV-susceptible (BALB/c ϫ B6)F 1 (CB6F 1 ) mice rapidly develop splenomegaly and succumb to leukemia within 2 months postinfection (pi), but they can be protected against FV by a single immunization with an F-MuLV-encoded CD4 ϩ T cell epitope, Env 462-479 (7). This vaccine-induced protection also requires B-lymphocytes, while FV-infected cells are eliminated in the absence of CD8 ϩ T cells (8). For the production of FV-neutralizing antibodies (Ab), CD11c ϩ dendritic cells and Myd88 that transduces signals from Toll-like receptors (TLR) are crucial (9). TLR7 senses retroviral entry (10) and inhibits virus replication over the first 5 days of infection through rapid production of nonneutralizing IgM (11). TLR7-deficient mice failed to generate germinal centers and IgM-negative (IgM Ϫ ) B cells upon FV infection (12), suggesting that immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR) are associated with neutralizing Ab production and FV control. To examine directly if SHM and CSR are required for FV neutralization, we utilized mice deficient in activation-induced cytidine deaminase (AID), a B cell-specific enzyme required for SHM and CSR (13).AID-deficient (AID Ϫ/Ϫ ) B6 and BALB/c mice were purchased from Riken BioResource Center, Tsukuba, Japan, and bred and maintained along with B cell-deficient MT/MT mice (5). Animal experiments were carried out in accordance with governmental and institutional regulations. To examine if SHM and CSR are required for Fv2-associated resistance, we infected wild-type (WT), MT/MT, and AID Ϫ/Ϫ B6 mice with 5,000 spleen focusforming units (SFFU) of FV that was free of lactate dehydrogenase-elevating virus (5). All MT/MT mice died within 20 weeks pi (Fig. 1A) without developing polycythemia (Fig. 1C), while AID Ϫ/Ϫ mice remained resistant. F-MuLV gp70 expression on expanding TER-119 Ϫ cells consistent with the development of F-MuLV-induced myeloid leukemia (5) was evident in MT/ MT but not in AID Ϫ/Ϫ mice (Fig. 1B). Thus, AID-mediated SHM and CSR are not required for F-MuLV elimination. Plasma viremia and virus-neutralizing Ab were detected as described previously (14). While MT/MT mice remained viremic even at 16 w...

Requirement for Fc Effector Mechanisms in the APOBEC3/Rfv3-Dependent Neutralizing Antibody Response

“…These results parallel data obtained for monoclonal bNAbs against HIV-1 (5, 6), suggesting that Fc␥R-mediated effector mechanisms are evolutionarily conserved processes for IgG-mediated retroviral clearance and play an important role even if multiple B cell epitopes are targeted simultaneously. Of note, our findings seemed at odds with a recent report that concluded that antibody class switching-and, by extension, IgG antibodies-is dispensable for recovery from FV infection (24). However, the first part of this study utilized B6 mice, which are Fv2 resistant and spontaneously recover.…”

A human inferred germline antibody binds to an immunodominant epitope and neutralizes Zika virus

“…Low levels of SHM in Abs possessing neutralizing activity have been previously reported in mice and humans [53][54][55], supporting the idea that germline-encoded mAbs can indeed neutralize. Abs with low levels of SHM have also been reported during the acute phase of human DENV infection, but it was not clear that these Abs contributed to the antiviral neutralization activity [56].…”

Memory B cell heterogeneity: Remembrance of things past

“…44,45 In contrast, mice that lack activation-induced cytidine deaminase, and therefore class-switched and mutated antibodies, are protected from these pathogens. [45][46][47] In fact, due to its unique attributes, IgM antibody may be particularly efficient at clearing bacteria or blood-resident infections.…”