Antibody-Dependent Cellular Phagocytosis of HIV-1-Infected Cells Is Efficiently Triggered by IgA Targeting HIV-1 Envelope Subunit gp41

Abstract

Antibodies mediate a broad array of non-neutralizing Fc-mediated functions against HIV-1 including antibody-dependent cellular cytotoxicity (ADCC) and antibodydependent cellular phagocytosis (ADCP). Accordingly, ADCC and ADCP induced by anti-HIV envelope gp120 IgG have been correlated to the limited success of the HIV-1 phase III vaccine trial RV144. It remains elusive whether ADCP can also be triggered by IgA, the isotype predominant at mucosal surfaces through which HIV-1 is mainly transmitted. Yet, we have previously shown that the HIV envelope subunit gp41-specific broadly neutralizing antibody 2F5 under the IgA isotype (2F5-IgA) triggers ADCC and cooperates with 2F5-IgG to increase HIV-1-infected cell lysis. Here, we now demonstrate that 2F5-IgA, more efficiently than 2F5-IgG, induces ADCP not only of gp41-coated beads but also of primary HIV-1-infected cells in a FcαRI-dependent manner. Both primary monocytes and neutrophils can act as effector cells of 2F5-IgA-mediated ADCP, although with different kinetics with faster neutrophil phagocytosis. However, unlike for ADCC, 2F5-IgA and 2F5-IgG do not cooperate to increase ADCP. Altogether, our results reveal that gp41-specific IgA mediate the efficient phagocytosis of HIV-1-infected cells. Inducing such ADCC and ADCP-prone IgA response by vaccination in addition to anti-HIV envelope IgG, might increase the protection against HIV acquisition at mucosal level.

IgA Potentiates NETosis in Response to Viral Infection

“…In serum, IgA is present at concentration of ~ 82-624 mg/dL, whereas IgG is found at ~ 694-1803 mg/dl 50 . In the context of HIV, mixed IgG/IgA:HIV ICs generated using the gp41-specific bnAb 2F5 cooperatively triggered ADCC of HIV-infected cells by monocytes, but did not act cooperatively to induce ADCP 33,51 . Likewise, we observed no cooperativity in the induction of NETosis when IgA and IgG were combined at a 1:1 ratio, or at physiological ratios.…”

“…In blood, IgA co-circulates with other antibodies, including IgG, which signals through distinct FcRs (FcγRs) and can also induce NETosis 32 . Mixed ICs composed of IgG/IgA:HIV have also been shown to act cooperatively to stimulate ADCC by monocytes 33 . We therefore tested whether mixed ICs composed of IAV bound by IgA and IgG together would influence the magnitude of NETosis induction relative to IgA alone.…”

Virosome-based nanovaccines; a promising bioinspiration and biomimetic approach for preventing viral diseases: A review

“…Also, the mucosal delivery dosage form of the HIV virosome vaccine could provide potent immune responses. The high HIV virulence route is through mucosal tissue; therefore, the initial mucosal antibody production is the substantial defense against HIV pathogens [ [75] , [76] , [77] ]. In the study, sublingual dosage form vaccine confronting HIV developed physical robustness, particles, and antigen integrity and stability.…”

IgA and FcαRI: Versatile Players in Homeostasis, Infection, and Autoimmunity

“…170 HIV-1 gp41 envelope-specific IgA additionally triggered ADCP of HIV-1 infected CD4 + T cells by monocytes and neutrophils more efficiently than anti-gp41 IgGs. 171 FcαRI-mediated neutrophil phagocytosis initiated by vaccine-induced IgA was associated with reduced risk of infection against simian immunodeficiency virus (SIV) after immunization via the nasal, but not the intramuscular route in non-human primates. 172 These studies may provide new insights into FcαRImediated immune responses against HIV-1 infected cells and address the potential functions of IgA during viral infections.…”