Background:  Simian immunodeficiency virus (SIV) hyperimmune serum (HIS), pooled from adult neonatal rhesus macaques (rhM) immunized with SIV_mac1A11, prevents infection of newborn rhM after oral challenge with pathogenic SIV_mac251. However, SIV-HIS does not neutralize the challenge strain, and the correlate of protection is unknown. We determined whether SIV-HIS could inhibit virus in the presence of rh peripheral blood mononuclear cell (PBMC) effector cells. We also determined the anti-viral activity of 3 non-neutralizing rhM monoclonal antibodies.

Methods:  CD8-depleted rh PBMC target cells were infected with SIV_mac251 for 48 hours, washed, and mixed with serial dilutions of SIV-HIS, SIV-IgG, or SIV-F(ab’)2. Autologous rh PBMC effector cells were then added at various E:T ratios. Five days later, p27 was measured in supernatant fluid by ELISA. To determine which specific cells among the rh PBMC were acting as effector cells, rh PBMC were depleted of CD8 or CD14⁺ cells. As above, 3 rhM monoclonal antibodies (3.10A, 3.11E, and C26) were tested, except that target cells consisted of SIV_mac251-infected CEM x 174 cells and effector cells were hu PBMC. 

Results:  In the absence of effector cells, SIV-HIS had little inhibitory activity against SIV_mac251, consistent with its poor neutralizing activity. However, in the presence of rh PBMC effector cells, there was inhibition of virus yield at dilutions as high as 1:12,800. SIV-IgG (made from SIV-HIS) inhibited virus in the presence of rh PBMC at concentrations as low as 2 μg/mL, whereas its F(ab’)2 had little activity. CD14⁺ cells (monocytes) were consistently involved as effector cells of anti-viral activity; CD8⁺ cells (likely natural killer cells) acted as effector cells in PBMC from some animals, but not from others. Monoclonal antibodies 3.10A and 3.11E, neither of which neutralizes SIV_mac251, gave means of 80% and 91% inhibition of SIV_mac251, respectively, at 20 μg/mL in the presence of hu PBMC effector cells. C26, which does not neutralize SIV_mac251, did not inhibit SIV_mac251 in the presence of hu PBMC.

Conclusions:  These results demonstrate, for the first time, that antibodies that do not neutralize pathogenic strains of SIV may nonetheless have potent anti-viral activity mediated by interactions between antibody Fc and Fc receptors on rhesus macaque cells, such as monocytes and natural killer cells. Since infusion of SIV-HIS prevents SIV_mac251 infection in the absence of neutralizing activity, these results suggest that antibody-dependent, cell-mediated virus inhibition is a protective immune function against primate lentivirus infection.