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    • Remarkably we show here that in HLA

    2018-11-07

    Remarkably, we show here that in HLA-B*57+ ECs, the frequency of Env-specific B cells, correlated positively with the breadth of viruses neutralized. Previous studies analyzed potential correlations between antibody secreting cells and Ab responses (Bussmann et al., 2010; Doria-Rose et al., 2009). We confirmed the findings from Bussman et al. that Env-specific B cell frequencies do not correlate with the Ab titers to Env in the sera of ECs (Bussmann et al., 2010). Doria-Rose et al. did not observe an association between the frequency of plasmablasts spontaneously secreting HIV-specific Abs and the breadth of neutralization (Doria-Rose et al., 2009). In our study, we focused on long-lived memory hcv protease inhibitors that provide not only an archive of contemporaneous HIV-specific Ab secreting cells but also of historic of Ab responses to the infection. In HLA-B*57+ ECs, we found a positive correlation between Env-specific memory B cell responses and the neutralizing breadth. However, it is important to note that this association was lost or correlated inversely when considering the global ECs population or HLA-B*57− ECs, respectively. Taking this study together with previously published work, we are proposing that in HLA-B*57+ ECs, an early and spontaneous control of viral replication (Goujard et hcv protease inhibitors al., 2009), probably mediated by CTL (Sáez-Cirión et al., 2007) and innate components of immunity (Barblu et al., 2012), might favor an early preservation of CD4+ Tfh cells and the establishment of efficient memory B cell responses sustaining the generation of potent antiviral responses including broad cross-neutralization. It is tempting to speculate that as recently observed in a unique HLA-B*57+ individual (Freund et al., 2017), broad neutralization in HLA-B*57+ ECs may also contribute to the control of HIV infection. Abs can also mediate antiviral functions independently of their ability to neutralize viruses, for instance through the binding of FcR and the initiation of ADCC. Interestingly, when comparing 9 nonneutralizing and 5 broadly neutralizing monoclonal Abs, a recent publication reported that bnAbs, due to their enhanced capacity to recognize HIV-infected cells, mediate more potent ADCC than non-neutralizing Abs (Bruel et al., 2017). However, in sera from patients, neutralization-independent Ab activities have been previously associated with long-term control of HIV infection (Lambotte et al., 2009; Lambotte et al., 2013; Baum et al., 1996). In particular, using HIV-infected cells, Lambotte et al. observed that HLA-B*57− ECs present significantly higher ADCC Ab titers than HLA-B*57+. They suggested that ADCC plays a role in the immune control of HIV, especially in HLA-B*57− ECs (Lambotte et al., 2013). In the present study, in HLA*B57− ECs, we reveal an inverse correlation between Env-specific memory B cell frequencies and the neutralization breadth. Therefore in both group of ECs, whether HIV-specific memory B cell frequency might be associated with the potency of non-neutralizing antiviral Ab functions, such as ADCC of infected cells, needs to be further addressed. In a study, using the sera of 9 controllers and 11 progressors, Smalls-Mantey et al. analyzed potential correlations between ADCC of infected cells and various parameters including neutralization (Smalls-Mantey et al., 2012). They observed similar ADCC Ab titers in both groups and did not find a correlation between ADCC and neutralization activities (Smalls-Mantey et al., 2012). However, the controler cohort was limited in size and they did not compare the ADCC and neutralization profiles based on the HLA-B genotype (Smalls-Mantey et al., 2012). Ackerman et al. proposed that the capacity to exert multiple antiviral functions might be linked to HIV-control (Ackerman et al., 2016). Indeed, depending on their isotype, Abs exert different antiviral functions. For instance, in contrast to IgG2 and IgG4, IgG1 and IgG3 bind strongly to FcR on phagocytic cells inducing efficient effector activity. Ackerman et al. showed that the sera from ECs exhibiting strong polyfunctional antiviral activities are enriched in Abs of IgG1 and IgG3 subtypes (Ackerman et al., 2016). In contrast, in viremic controllers, anti-HIV IgG2 production has been previously associated with HIV-control and slow progression (Martinez et al., 2005; Ngo-Giang-Huong et al., 2001). In this work, we show that in ECs, Env-specific memory B cell responses were mainly composed of IgG1 Abs. Only few ECs presented IgG2+ or IgG3+ responses. Interestingly in HLA-B*57+ ECs, Env-specific IgG3+ memory B cell frequencies correlated positively with both total IgG and IgG1 Env-specific responses. In contrast, in HLA-B*57− ECs, Env-specific IgG3+ memory B cell frequencies were negatively associated with the neutralization breadth of HIV. These observations suggest that depending on the HLA genotype (e.g. HLA-B*57+/−) different Ab isotypes and/or functions might be involved in immune control of HIV infection.