Cell-to-cell spread-blocking activity is extremely limited in the sera of HSV-1 and HSV-2 infected subjects

Herpes Simplex Virus (HSV) 1 and 2 can evade serum antibody-mediated neutralization through cell-to-cell transmission mechanisms, which represent one of the central steps in disease reactivation. To address the role of humoral immunity in controlling HSV-1 and HSV-2 replication, we analyzed serum samples from 44 HSV-1 and HSV-2 seropositive subjects by evaluating: (i) their efficiency in binding both the purified viral particles and recombinant gD and gB viral glycoproteins, (ii) their neutralizing activity and (iii) their capability to inhibit the cell-to-cell virus passage in vitro All of the sera were capable of binding the gD, the gB and whole virions and all sera significantly neutralized cell-free virus. However, neither whole sera, nor purified serum IgG fraction were able to inhibit significantly cell-to-cell virus spreading in in vitro post-virus-entry infectious assays. Conversely, when spiked with an already described anti-gD human monoclonal neutralizing antibody capable of inhibiting HSV-1 and -2 cell-to-cell transmission, each serum boosted both its neutralizing and post-virus-entry inhibitory activity, with no interference exerted by serum antibody subpopulations.Importance: Despite its importance in the physiopathology of Herpes Simplex Virus type 1 and 2 infections, the cell-to-cell spreading mechanism is still poorly understood. The data shown here suggests that infection-elicited neutralizing antibodies capable of inhibiting cell-to-cell virus spread can be under represented in most infected subjects. These observations can be of great help in better understanding the role of humoral immunity in controlling virus reactivation and in the perspective of developing novel therapeutic strategies, studying novel correlates of protection, and designing effective vaccines.