Deciphering Fc-mediated Antiviral Antibody Functions in Animal Models

Schmaljohn, Alan L.; Orlandi, Chiara; Lewis, George K.

-ADCC as measured (17) for example by: direct lysis of infected cells; trogocytosis (RFADCC); phagocytosis; granzyme release/signaling by NK -Complement activation: lytic cascade; other pleotropic effects of partial complement activation • many other potential interactions * See Box 1 for meaning of the term "Protection" in this manuscript. For discussions and additional references on these phenomena, refer to past reviews (4, 5). FIGURE 2 | Adaptive immunity at the cellular level, and windows of opportunity. As virus enters cells (here at a multiplicity of infection around 1 infectious unit [IU] per cell, thus non-infectious particles at even higher ratios), disassembles, and then makes new proteins and genomes on the way to making more virions, the targets available to the immune system change. Conventionally, "neutralizing Abs" inactivate or sequester virus extracellularly, either before infection or as virus emerges. FcR-bearing cells can facilitate such extracellular clearance when the FcR-bearing cells are virus-resistant, and additional proteins-such as those of the complement cascade-can augment this opsonization. Before and during viral replication, either T cells (recognizing MHC-associated peptides) or cell-targeting Abs (CTAbs, recognizing emergent and pre-assembly proteins) can disrupt cell integrity and thereby diminish the viral yield per cell (burst size) by many-fold; the sparing of uninfected cells accrues exponentially. In some cases (well-described with HIV), the entering virions display new and early CTAb targets (*) as the viral spike rearranges coincident with receptor engagement. Emphasis in this manuscript is upon recent and emerging experimental tools to decipher the in vivo effects of Fc-FcR interactions that result in protection, including those involving Abs shown to score positively with in vitro neutralization assays, ADCC assays, or both.