In VivoAdministration of CD4-Specific Monoclonal Antibody: Effect on Provirus Load in Rhesus Monkeys Chronically Infected with the Simian Immunodeficiency Virus of Macaques

Abstract

Since monoclonal antibodies (MAb) specific for CD4 are potent inhibitors of HIV and SIV replication in vitro, we explored their potential usefulness in vivo as an AIDS therapy. The anti-CD4 MAb 5A8 binds to domain 2 of the CD4 molecule and inhibits virus replication and virus-induced cell fusion at a postvirus binding step. Administration of this MAb to normal rhesus monkeys coats all circulating and lymph node CD4 cells and induces neither CD4 cell clearance nor measurable immunosuppression. In the present study, monkeys chronically infected with the simian immunodeficiency virus of macaques (SIVmac) had stable levels of SIVmac provirus in PBMC prior to treatment as measured by a quantitative polymerase chain reaction technique. Six infected monkeys treated with anti-CD4 MAb demonstrated a significant decrease in SIVmac provirus level after 9 days. Of these monkeys, 3 had > 800 CD4 cells/microliter and developed strong antimouse Ig responses that prevented further treatment. The remaining 3 monkeys had < 800 CD4 cell/microliter and failed to develop antimouse Ig antibody responses. When treatment was continued for 12-21 days in these monkeys, a sustained or further decrease in SIVmac provirus load occurred over the extended treatment period. Four monkeys that received a control MAb of irrelevant specificity for 9-22 days showed either no significant change or a transient increase in SIVmac provirus. Thus, the passive administration of anti-CD4 MAb may exert a specific antiviral effect in controlling immunodeficiency virus infection in vivo.

Gene-Based Vaccination with a Mismatched Envelope Protects against Simian Immunodeficiency Virus Infection in Nonhuman Primates

“…S1 in the supplemental material). This result suggests that anti-CD4 antibodies or antibodies to the producer 293 cells were not responsible for the vaccine protective effect seen in previous studies (5,37). In addition, because antibody responses to viral Env were shown to correlate with protection, it is likely that antibodies to HIV-1 Env mediate this effect.…”

Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor

“…It remains possible that ibalizumab could have different protective efficacy against SHIV challenge, but no animal model protection studies have yet been published that demonstrate such efficacy. Ibalizumab is derived from a mouse mAb 5A8 that was shown to have a therapeutic effect in chronically SIV-infected macaques (47). Likewise, ibalizumab reduced viremia after infusion into HIV-1–infected subjects (35, 36).…”

Synergistic In Vitro Antiretroviral Activity of a Humanized Monoclonal Anti-CD4 Antibody (TNX-355) and Enfuvirtide (T-20)

“…The 5A8 antibody does not result in the clearance of CD4 cells in vivo and does not measurably interfere with CD4 cell function (1,(9)(10)(11)(12). This demonstration of the in vivo antiretroviral activity of TNX-355 raises the possibility that a novel step in the entry process may be exploited in the development of antiretroviral chemotherapeutic approaches that might be of particular utility in patients with viral strains that have developed resistance to antiviral drugs directed at the viral reverse transcriptase and/or serine protease.…”