br Funding This work was funded by the National Institutes

Funding This work was funded by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) contract HHSN272200800047C to EP. The Kawempe Community Health Study was funded entirely by the Tuberculosis Research Unit (grant N01-AI95383 and HHSN266200700022C/N01-AI70022 from the National Institutes of Health National Institute of Allergy and Infectious Diseases, awarded to WHB). CMB is supported by a grant from the NIH/NCRR CTSA KL2TR000440.
Author Contributions
Conflicts of Interest
Acknowledgements
Introduction HIV-1 (HIV) infection alters B cell differentiation resulting in spontaneous immunoglobulin secretion, hypergammaglobulinemia (Lane et al., 1983) and decrease in memory B cell frequencies (Moir et al., 2008; Hu et al., 2015; Buckner et al., 2013). HIV-specific 5-Iodotubercidin cost (Abs), with the capacity to neutralize the autologous virus, appear several months after infection. However, these Abs poorly neutralize heterologous HIV strains (Tomaras et al., 2008; Moog et al., 1997; Wei et al., 2003; Deeks et al., 2006; Richman et al., 2003; Gray et al., 2007). Cross-reactive neutralizing Abs, are produced only 2 to 4years after seroconversion (Gray et al., 2011; Mikell et al., 2011; Richman et al., 2003) and at low titers in most individuals (Hraber et al., 2014). Only 20% of patients harbor high titers of cross-reactive neutralizing Abs (Doria-Rose et al., 2010). Among them, 1% were identified as elite neutralizers based on the capacity of their plasma to neutralize, across clades, a large panel of HIV strains (Li et al., 2007; Simek et al., 2009). Broadly neutralizing monoclonal Abs (bnAbs) were cloned from HIV-specific memory B cells isolated from these patients (Scheid et al., 2009; Mouquet, 2014; Sok and Burton, 2016). Understanding how these bnAbs are generated in HIV-infected individuals could lead the path to the development of an antibody-based vaccine. In viremic patients, the breadth of neutralization has been associated with higher viral loads (Doria-Rose et al., 2010; Piantadosi et al., 2009; Deeks et al., 2006; Sajadi et al., 2011; Doria-Rose et al., 2009; Sather et al., 2009; Rodriguez et al., 2007), duration of viral exposure and viral diversity (Rusert et al., 2016). HIV-infected individuals who naturally control HIV infection without combined antiretroviral therapy (cART) (Saez-Cirion and Pancino, 2013), in particular elite controllers (ECs, <1% of HIV-infected individuals) who maintain very low to undetectable viremia (Lambotte and Delfraissy, 2005; Grabar et al., 2009) represent a unique chance to study immune responses potentially involved in viral suppression (Walker and Yu, 2013). A fraction of ECs exhibit potent cytotoxic CD8+ T cell responses against HIV-infected cells (Sáez-Cirión et al., 2007; Betts et al., 2006; Hersperger et al., 2011), often associated with the expression of the HLA-B*57 allele (Migueles et al., 2000; Lambotte and Delfraissy, 2005; Betts et al., 2006). HIV-specific CD4+ T cells of ECs express high avidity T cell receptors (TCRs) suggesting that T cell helper responses contribute to HIV-control (Benati et al., 2016). In contrast, several studies have shown that ECs present lower cross-neutralizing Ab responses as compared to viremic individuals (Lambotte et al., 2009; Pereyra et al., 2008; Bailey et al., 2006; Sajadi et al., 2011). However, among ECs, there is a marked heterogeneity, some presenting broad cross-neutralizing capacities while others show minimal or no neutralization (Lambotte et al., 2009; Scheid et al., 2009; Pereyra et al., 2008; Bailey et al., 2006; Sajadi et al., 2011). Non-neutralizing Ab responses might also exert significant antiviral activities (Chung et al., 2015). In particular, titers of Abs executing antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be higher in ECs (Lambotte et al., 2009) and predominant in HLA-B*57− ECs as compared to HLA-B57+ ECs (Lambotte et al., 2013). More recently, HIV-control has been linked to the capacity of the sera from ECs to perform multiple effector functions (Ackerman et al., 2016). Indeed, depending on their isotype, Abs exhibit different effector functions such as Fcγ receptors (FcγR) binding, initiation of ADCC and activation of the complement cascades. Although the immunoglobulin G1 (IgG1) subclass dominates HIV-specific responses, the proportion of IgG isotypes might vary depending on individuals, the HLA status and the clinical parameters (Binley et al., 2008, Banerjee et al., 2010, Ackerman et al., 2016, French et al., 2013). Ackerman et al. showed that the sera from ECs exhibiting strong polyfunctional antiviral activities are enriched in Abs of IgG1 and IgG3 subclasses (Ackerman et al., 2016). IgG2 Abs to the HIV Gag protein have been associated with long-term nonprogression (Martinez et al., 2005; Ngo-Giang-Huong et al., 2001) and seem more abundant in HLA-B*57− ECs compared to HLA-B*57+ ECs (French et al., 2013). Therefore, the quality of Ab responses, defined by the diversity of Ab subclasses should be considered when characterizing Ab responses elicited by HIV infection and vaccine candidates.