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Cellular proteins, including major histocompatibility complex (MHC) class I and class II antigens, are incorporated into the membrane of HIV-1 when virions bud from infected cells. Experiments were performed to determine whether human sera that contained MHC class I and/or class II antibodies would lyse or neutralize a primary isolate of HIV. These results demonstrate that in the presence of complement, sera from some alloimmunized persons mediated significant anti-viral activity against an HIV primary isolate. Both lysis and neutralization of virus were observed. The antiviral effects were complement dependent because heat inactivation eliminated most anti-viral effects. Antiviral activity mediated by sera containing MHC alloantibodies in the presence of complement was ≥ activity due to sera from HIV-infected persons as reported in this and a previous study. High levels of antibodies to both MHC class I and class II were present in sera that mediated the highest levels of antiviral activity. Absorption of serum with platelets (which express class I but not class II antigens) substantially reduced their lytic activity. These studies suggest that MHC antibodies mediate potent anti-viral effects on primary isolates of HIV and support the possibility that deliberately alloimmunizing humans might protect against HIV infection.