The human immunodeficiency virus (HIV) causes severe immune deficiency in humans and over 7,000 people are infected everyday [
1]. The key to resistance to HIV infection and disease progression resides within the host immune system that consists of two major defense pathways: innate and adaptive immunity [
2]. There is a growing recognition that the complement system contributes to HIV replication and pathogenesis [
3,
4]. In fact, as a first line of defense against pathogenic microorganisms and a mediator between the innate and adaptive immune responses, the complement system is a particular focus of these immune-evasion strategies [
4‐
6]. In human plasma, HIV immediately activates the complement system, even in the absence of HIV-specific antibodies [
7]. After seroconversion, the presence of HIV-specific antibodies triggers further activation of the classical complement pathway [
11]. Complement activation would be harmful to the virus if the reactions were allowed to go to completion, since their final outcome would be virolysis. HIV, however, has evolved several mechanisms to evade complement-mediated lysis (CoML) and exploit the complement system to enhance viral infectivity [
8]. This may be critical, as during opsonization, high amounts of C3-fragments are deposited on the surface of HIV. Also, binding of C3-fragments to gp120 reduces the accessibility of the viral envelope protein [
9]. Current therapies for HIV infection using highly active antiretroviral therapy (HAART) are not able to completely eliminate virus and complications of these therapies include severe side effects and viral resistance that may establish latent reservoirs of HIV. There remains a need to develop novel treatments for infected individuals who may no longer respond to or who have significant toxicity from antiretroviral therapy and to prevent HIV transmission [
10]. To this end, bispecific antibody (BsAb) constructs may be used to target HIV and infected cells for destruction, resulting in greater control and prevention of infection. We previously reported a targeted complement activator [
11], CR2-Fc, and the results shown that CR2-Fc can enhance lysis of HIV (data not show). However, the targets of CR2-Fc are C3d and C3dg, which can be distributed widely when complicating other diseases. Thus, it is interesting to know whether target to HIV envelope could improve the anti-virus efficacy of complement. Here, we hypothesize that a bispecific, trifunctional antibody construct incorporating the disulfide-stabilized Fv fragments (dsFv) against gp120, the dsFv against C3d and Fc promotes destruction of HIV type 1 (HIV-1) by complement.