Rhesus Macaque Polyclonal and Monoclonal Antibodies Inhibit Simian Immunodeficiency Virus in the Presence of Human or Autologous Rhesus Effector Cells

Abstract

Although antibodies can prevent or modulate lentivirus infections in nonhuman primates, the biological functions of antibody responsible for such effects are not known. We sought to determine the role of antibodydependent cell-mediated virus inhibition (ADCVI), an antibody function that inhibits virus yield from infected cells in the presence of Fc receptor-bearing effector cells, in preventing or controlling SIVmac251 infection in rhesus macaques (Macaca mulatta). Using CEMx174 cells infected with simian immunodeficiency virus mac251 (SIVmac251), both polyclonal and monoclonal anti-SIV antibodies were capable of potent virus inhibition in the presence of human peripheral blood mononuclear cell (PBMC) effector cells. In the absence of effector cells, virus inhibition was generally very poor. PBMCs from healthy rhesus macaques were also capable of mediating virus inhibition either against SIVmac251-infected CEMx174 cells or against infected, autologous rhesus target cells. We identified both CD14 ؉ cells and, to a lesser extent, CD8 ؉ cells as the effector cell population in the rhesus PBMCs. Finally, pooled, nonneutralizing SIV-antibody-positive serum, shown in a previous study to prevent infection of neonatal macaques after oral SIVmac251 challenge, had potent virus-inhibitory activity in the presence of effector cells; intact immunoglobulin G, rather than F(ab) 2 , was required for such activity. This is the first demonstration of both humoral and cellular ADCVI functions in the macaque-SIV model. ADCVI activity in nonneutralizing serum that prevents SIV infection suggests that ADCVI may be a protective immune function. Finally, our data underscore the potential importance of Fc-Fc receptor interactions in mediating biological activities of antibody.

Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

“…This discordance might be explained by the fact that the panel used for neutralizing assays did not include the strains used in our ADCVI assays. However, discordance between ADCVI or ADCC and neutralizing activities has been observed previously and may be due to differences in antigenic targets or in the subclass distribution of the two functional Ab responses (13,30,31). Alternatively, the Ag-Ab affinity required for ADCVI might be less than that required for neutralization because ADCVI Ab need not block virus-receptor interactions.…”

“…One explanation for the discordance between ADCVI activity and the other Abs is our use of a clinical R5 strain of HIV-1 grown in PBMCs (46). Additionally, we and others (13,30,31) have shown that functional Ab responses directed against infected cells and requiring Fc-Fc␥R interactions do not necessarily correlate with neutralizing or binding Ab levels; our current results further underscore the fact that Ab functions are not necessarily predictable from binding assays and that assays used to measure one function might not predict another.…”

“…We previously showed that ADCVI Abs arise early and correlate inversely with the viremia level during acute HIV infection (11). Nonneutralizing anti-SIV-Ab that prevents infection of neonatal macaques after oral SIV mac251 challenge has potent ADCVI activity (13); in the absence of other Ab functions, it is likely that ADCVI accounted for this protection. Recently, a vaccine-induced reduction in acute SIV viremia was shown to correlate with the ADCC Ab response to the vaccine (32).…”

“…ADCVI Ab is measurable early during acute HIV infection and correlates inversely with plasma viral load (11). ADCVI Abs are also elicited by infection or immunization with SIV (13). Finally, nonneutralizing Ab that prevents SIV mac251 infection after oral challenge of newborn rhesus macaques has potent ADCVI activity against the challenge strain (13).…”

HIV/AIDS: 30 Years of progress and future challenges

“…By this process, antiviral antibodies bind to infected cells that are killed by NK cells and neutrophils. A protective role of ADCC, but not NAbs, has been reported in macaques that were vaccinated for SIV [74]. Still, a recent study suggests that HIV can also escape from ADCC [75].…”