Technical description
In ADE, antiviral antibodies promote viral infection of target immune cells by exploiting the phagocytic FcγR or complement pathway.[5] After interaction with a virus, the antibodies bind Fc receptors (FcR) expressed on certain immune cells or complement proteins. FcγRs bind antibodies via their fragment crystallizable region (Fc).
The process of phagocytosis is accompanied by virus degradation, but if the virus is not neutralized (either due to low affinity binding or targeting to a non-neutralizing epitope), antibody binding may result in virus escape and, therefore, more severe infection. Thus, phagocytosis can cause viral replication and the subsequent death of immune cells. Essentially, the virus “deceives” the process of phagocytosis of immune cells and uses the host's antibodies as a Trojan horse.
ADE may occur because of the non-neutralizing characteristic of an antibody, which binds viral epitopes other than those involved in host-cell attachment and entry. It may also happen when antibodies are present at sub-neutralizing concentrations (yielding occupancies on viral epitopes below the threshold for neutralization),[6][7] or when the strength of antibody-antigen interaction is below a certain threshold.[8][9] This phenomenon can lead to increased viral infectivity and virulence.
ADE can occur during the development of a primary or secondary viral infection, as well as with a virus challenge after vaccination.[1][10][11] It has been observed mainly with positive-strand RNA viruses, including flaviviruses such as dengue, yellow fever, and Zika;[12][13][14] alpha- and betacoronaviruses;[15] orthomyxoviruses such as influenza;[16] retroviruses such as HIV;[17][18][19] and orthopneumoviruses such as RSV.[20][21][22] The viruses that cause it frequently share common features such as antigenic diversity, replication ability, or ability to establish persistence in immune cells.[1]
The mechanism that involves phagocytosis of immune complexes via the FcγRII/CD32 receptor is better understood compared to the complement receptor pathway.[23][24][25] Cells that express this receptor are represented by monocytes, macrophages, and some categories of dendritic cells and B-cells. ADE is mainly mediated by IgG antibodies,[24] but IgM[26] and IgA antibodies[18][19] have also been shown to trigger it.