Impact of IgA Constant Domain on HIV-1 Neutralizing Function of Monoclonal Antibody F425A1g8

Abstract

With the majority of HIV infections resulting from mucosal transmission, induction of an effective mucosal immune response is thought to be pivotal in preventing transmission. HIV-specific IgA, but not IgG, has been detected in genital tract, seminal fluid, urethral swabs, urine and vaginal wash samples of HIV-negative sex workers and HIV-status discordant couples. Purified mucosal and plasma IgA from some individuals with highly exposed, persistently sero-negative (HEPS) can neutralize infection and present cross-clade neutralization activity though present at low levels. We generated a CD4i human monoclonal antibody (mAb) F425A1g8 and characterized the impact of its isotype variants on HIV neutralizing activity. The result showed that, in contrast to little neutralization by the F425A1g8 IgG1 in the absence of sCD4, the IgA1 variant of the antibody (Ab) displayed significant independent neutralization activity against a range of HIV clade B isolates in the absence of sCD4. The studies of the neutralizing function of IgA isotypes, and the functional relationship between different antigenic epitopes and IgA antibodies, may also suggest strategies for the intervention of virus transmission and spread within the mucosa of host, as well as serve to inform the design of vaccine strategies that may be more effective at preventing mucosal transmission. This research clearly suggests that IgA isotype because of its unique molecular structure may play an important role in HIV neutralization.

Broadly neutralizing antibodies suppress post-transcytosis HIV-1 infectivity

“…For this reason, we produced selected bNAbs as recombinant IgG and IgA1/IgA2 monoclonal antibodies. In contrast to what was reported in previous works, 46,54,55 we showed that swapping the bNAbs' Fc region from IgG to IgA did not substantially modify or alter their affinities, targeted epitopes or antiviral inhibitory activities. When applied with or without virus at the surface of the epithelial monolayers, we observed that a similar fraction of purified IgG and IgA was transported to the basal pole, likely in a FcRn-independent manner.…”

IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

“…Monomeric MAb362 IgA1 was also co-expressed with J chain to produce dimeric IgA, which further improved neutralization ( Figure 4b ). This is consistent with our prior study showing isotype switch to IgA1 lead to improved antibody neutralization of HIV infection 25 Our data extends this observation to coronavirus, suggesting that IgA may play an important role in SARS-CoV-2 neutralization.…”

Co-Administration of Lipid Nanoparticles and Sub-Unit Vaccine Antigens Is Required for Increase in Antigen-Specific Immune Responses in Mice

“…While some reports have characterized the advantage of using nanoparticles to encapsulate/deliver antigens and TLR agonists such as PolyIC to induce strong antigen-specific CD8+ T cell responses [18,19], our LNPs do not require the encapsulation of TLR agonists or antigen to stimulate strong antigen-specific immune responses [17]. However, the specific requirement for the co-administration of LNPs and antigen and the specific formulation characteristics that dictate the successful generation of strong antigen-specific immune responses by LNPs were not evaluated.…”