Viral multiplicity of attachment and its implications for human immunodeficiency virus therapies

Abstract

The multiplicity of attachment (MOA) of a virion in any particular time interval is the average number of cellular attachment opportunities that must be blocked to keep the virion in suspension. MOA is usually proportional to incubation time and cell concentration. Low MOA (like low multiplicity of infection) is required for reproducible assay of adsorptive blockers, and high MOA by itself can produce spurious synergies between adsorptive blockers, e.g., soluble CD4 (sCD4) and some antibodies. Poliovirus and human immunodeficiency virus (HIV) data show that viral neutralization conforms quantitatively to MOA and kinetic theory over large ranges of incubation times and target cell concentrations. Extrapolating sCD4 data beyond conditions achievable in vitro to those in vivo predicts that sCD4 concentrations above the strain-specific sCD4-gp120 dissociation constant are required to block lymphoid HIV significantly, in at least semiquantitative agreement with clinical results. The extrapolation is applicable to humoral neutralization data as well. MOA analysis also indicates that although completely stopping the attachment of individual virions to cells may still be an effective therapeutic strategy against established HIV infection, merely retarding attachment probably is not. The concept of MOA holds great promise for improving the therapeutic relevance of in vitro data and can be applied to any infectious agent, to many processes that impair or enhance infection steps, and to many assay end points, not just infection.