A Humanized, Nondepleting Anti-CD4 Antibody That Blocks Virus Entry Inhibits Virus Replication in Rhesus Monkeys Chronically Infected with Simian Immunodeficiency Virus

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Abstract
Therapeutic approaches that interfere with viral entry hold promise in preventing or treating HIV infection. Hu5A8, a humanized monoclonal antibody against CD4, was previously shown to inhibit HIV and SIV replication in vitro and was safely administered to rhesus monkeys without depleting CD4+ T cells. This antibody completely suppressed replication of six different SIVmac 251 primary isolates in vitro. Twice weekly administration of 3-mg/kg doses of hu5A8 for 2 to 4 weeks to SIV-infected rhesus monkeys resulted in sustained plasma antibody levels of ≥20 μg/ml during treatment and 5- to 50-fold decreases in plasma viremia, although suppression of viral replication was transient. Two of three treated monkeys developed antibody responses against the administered monoclonal antibody. Loss of antiviral effect was not temporally associated with anti-hu5A8 antibody responses or due to activation of CD4+ T cells by hu5A8. However, SIV isolated after hu5A8 treatment was approximately 5-fold more resistant to suppression by hu5A8 than SIV isolates obtained from the same monkeys before treatment. The rapid development of resistance may have resulted from SIV variants that infect cells by a CD4-independent mechanism. These results support the overall concept of anti-CD4 monoclonal antibody treatment to suppress AIDS virus replication in vivo while demonstrating important issues as to its clinical feasibility.