Abstract:Antiretroviral neutralizing antibody (NAb) responses are often evaluated in the absence of Fc-dependent immune effectors. In murine Friend retrovirus infection, Apobec3/Rfv3 promotes a potent polyclonal NAb response. Here, we show that the Apobec3/Rfv3-dependent NAb response correlated with virus-specific IgG2 titers and that thein vivoneutralization potency of Apobec3/Rfv3-resistant antisera was dependent on activating Fcγ receptors but not complement. The data strengthen retroviral vaccine strategies aimed a… Show more
“…To test if mA3/Rfv3-mediated enhancement of NAb responses occurs in LDV-free FV infection, WT and mA3 KO mice were infected with 10 4 SFFU of FV/LDV or FV and plasma NAb levels were evaluated at 28 dpi. Consistent with our previously published data [10, 25], mA3 KO mice had significantly lower NAb titers (3.4-fold) compared to WT mice during FV/LDV co-infection (Fig. 3a).…”
Section: Resultssupporting
confidence: 93%
“…In contrast to FV/LDV infections showing that mA3 influences NAb responses in the B6 background (Fig. 3a) [10, 25], the NAb titers between IFNAR KO and IFNAR/mA3 KO mice were not significantly different from each other (Fig. 4a).Fig.…”
BackgroundAPOBEC3/Rfv3 restricts acute Friend retrovirus (FV) infection and promotes virus-specific neutralizing antibody (NAb) responses. Classical Rfv3 studies utilized FV stocks containing lactate-dehydrogenase elevating virus (LDV), a potent type I interferon inducer. Previously, we showed that APOBEC3 is required for the anti-FV activity of exogenous IFN-alpha treatment. Thus, type I interferon receptor (IFNAR) signaling may be required for the APOBEC3/Rfv3 response.ResultsTo test if the APOBEC3/Rfv3 response is dependent on type I IFN signaling, we infected IFNAR knockout versus IFNAR/APOBEC3 double-knockout mice with FV/LDV or LDV-free FV, and evaluated acute FV infection and subsequent NAb titers. We show that LDV co-infection and type I IFN signaling are not required for innate APOBEC3-mediated restriction. By contrast, removal of LDV and/or type I IFN signaling abrogated the APOBEC3-dependent NAb response.ConclusionsAPOBEC3 can restrict retroviruses in a type I IFN-independent manner in vivo. By contrast, the ability of APOBEC3 to promote NAb responses is type I IFN-dependent. These findings reveal novel insights on the interplay between type I IFNs and APOBEC3 in vivo that may have implications for augmenting antiretroviral NAb responses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0349-2) contains supplementary material, which is available to authorized users.
“…To test if mA3/Rfv3-mediated enhancement of NAb responses occurs in LDV-free FV infection, WT and mA3 KO mice were infected with 10 4 SFFU of FV/LDV or FV and plasma NAb levels were evaluated at 28 dpi. Consistent with our previously published data [10, 25], mA3 KO mice had significantly lower NAb titers (3.4-fold) compared to WT mice during FV/LDV co-infection (Fig. 3a).…”
Section: Resultssupporting
confidence: 93%
“…In contrast to FV/LDV infections showing that mA3 influences NAb responses in the B6 background (Fig. 3a) [10, 25], the NAb titers between IFNAR KO and IFNAR/mA3 KO mice were not significantly different from each other (Fig. 4a).Fig.…”
BackgroundAPOBEC3/Rfv3 restricts acute Friend retrovirus (FV) infection and promotes virus-specific neutralizing antibody (NAb) responses. Classical Rfv3 studies utilized FV stocks containing lactate-dehydrogenase elevating virus (LDV), a potent type I interferon inducer. Previously, we showed that APOBEC3 is required for the anti-FV activity of exogenous IFN-alpha treatment. Thus, type I interferon receptor (IFNAR) signaling may be required for the APOBEC3/Rfv3 response.ResultsTo test if the APOBEC3/Rfv3 response is dependent on type I IFN signaling, we infected IFNAR knockout versus IFNAR/APOBEC3 double-knockout mice with FV/LDV or LDV-free FV, and evaluated acute FV infection and subsequent NAb titers. We show that LDV co-infection and type I IFN signaling are not required for innate APOBEC3-mediated restriction. By contrast, removal of LDV and/or type I IFN signaling abrogated the APOBEC3-dependent NAb response.ConclusionsAPOBEC3 can restrict retroviruses in a type I IFN-independent manner in vivo. By contrast, the ability of APOBEC3 to promote NAb responses is type I IFN-dependent. These findings reveal novel insights on the interplay between type I IFNs and APOBEC3 in vivo that may have implications for augmenting antiretroviral NAb responses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0349-2) contains supplementary material, which is available to authorized users.
“…Since CD8 + and CD4 + T cell responses were similar in FV-infected and co-infected mice, we next analysed the humoral response against the FV helper virus F-MuLV. Protective humoral responses during FV infection are mainly mediated by antibodies of the IgG2 subclass [50] and a beneficial effect of neutralising antibodies in the control of FV was described before [27–29, 51–53]. Thus, we measured F-MuLV-specific IgG in the serum of FV-infected and L .…”
Worldwide more than 2 billion people are infected with helminths, predominantly in developing countries. Co-infections with viruses such as human immunodeficiency virus (HIV) are common due to the geographical overlap of these pathogens. Helminth and viral infections induce antagonistic cytokine responses in their hosts. Helminths shift the immune system to a type 2-dominated immune response, while viral infections skew the cytokine response towards a type 1 immune response. Moreover, chronic helminth infections are often associated with a generalized suppression of the immune system leading to prolonged parasite survival, and also to a reduced defence against unrelated pathogens. To test whether helminths affect the outcome of a viral infection we set up a filarial/retrovirus co-infection model in C57BL/6 mice. Although Friend virus (FV) infection altered the L. sigmodontis-specific immunoglobulin response towards a type I associated IgG2 isotype in co-infected mice, control of L. sigmodontis infection was not affected by a FV-superinfection. However, reciprocal control of FV infection was clearly impaired by concurrent L. sigmodontis infection. Spleen weight as an indicator of pathology and viral loads in spleen, lymph nodes (LN) and bone marrow (BM) were increased in L. sigmodontis/FV-co-infected mice compared to only FV-infected mice. Numbers of FV-specific CD8+ T cells as well as cytokine production by CD4+ and CD8+ cells were alike in co-infected and FV-infected mice. Increased viral loads in co-infected mice were associated with reduced titres of neutralising FV-specific IgG2b and IgG2c antibodies. In summary our findings suggest that helminth infection interfered with the control of retroviral infection by dampening the virus-specific neutralising antibody response.
“…Sequence comparisons of monoclonal antibodies from Rfv3resistant versus Rfv3-susceptible mice suggested that protective neutralizing antibodies are associated with the IgG2c subclass, specific V H gene families, increased binding affinity to virions and higher somatic mutations (Halemano et al 2014). In passive transfer studies, the neutralizing activity of the antibodies was shown to be dependent on activating Fcγ receptors, but not on complement (Halemano et al 2015).…”
Section: B Cell Responses and Antibodiesmentioning
Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type I interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feedback mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.
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