Abstract
Bispecific HIVxCD3 DART molecules that co-engage the viral envelope glycoprotein (Env) on HIV-1-infected cells and the CD3 receptor on CD3+ T cells are designed to mediate the cytolysis of HIV-1-infected, Env-expressing cells. Using a novel ex vivo system with cells from rhesus macaques (RMs) infected with a chimeric Simian-Human Immunodeficiency Virus (SHIV) CH505 and maintained on ART, we tested the ability of HIVxCD3 DART molecules to mediate elimination of in vitro-reactivated CD4+ T cells in the absence or presence of autologous CD8+ T cells. HIVxCD3 DART molecules with the anti-HIV-1 Env specificities of A32 or 7B2 (non-neutralizing antibodies) or PGT145 (broadly neutralizing antibody) were evaluated individually or combined. DART molecule-mediated antiviral activity increased significantly in the presence of autologous CD8+ T cells. In this ex vivo system, the PGT145 DART molecule was more active than the 7B2 DART molecule, which was more active than the A32 DART molecule. A triple combination of the DART molecules exceeded the activity of the individual PGT145 DART molecule. Modified quantitative virus outgrowth assays confirmed the ability of the DART molecules to redirect RM CD3+ T cells to eliminate SHIV-infected RM CD4+ T cells as demonstrated by the decreased propagation of in vitro infection by the infected cells pre-incubated with DART molecules in presence of effector CD8+ T cells. While mediating cytotoxic activity, DART molecules did not increase proinflammatory cytokine production. In summary, combination of HIVxCD3 DART molecules that have broadly-neutralizing and non-neutralizing anti-HIV-1 Env specificities can leverage the host immune system for treatment of HIV-1 infection but will require appropriate reactivation of the latent reservoir.
Highlights
Since the first reported cases of Acquired Immunodeficiency Syndrome (AIDS) in 1981, infection with Human Immunodeficiency Virus type 1 (HIV-1) has been deemed a global and persistent epidemic
All three HIVxRSV DART molecules demonstrated binding to the Simian-Human Immunodeficiency Virus (SHIV).CH505.375H-infected A66 cells as shown by the frequency (%p27+/DART+) and median fluorescent intensity (MFI) of infected cells bound by the DART molecules (Figures 1A, B)
The killing activity of HIVxCD3 DART molecule, which requires binding to both target and effector cells, occurs at EC50 values that range from 110 ng/mL [33]
Summary
Since the first reported cases of Acquired Immunodeficiency Syndrome (AIDS) in 1981, infection with Human Immunodeficiency Virus type 1 (HIV-1) has been deemed a global and persistent epidemic. The treatment of HIV-1 infection with antiretroviral therapy (ART) has been effective in controlling virus replication, delaying disease progression, and reducing HIV-1 transmission [1]. The inability of ART to eradicate HIV-1 infection is primarily due to the establishment of a latent reservoir that cannot be successfully targeted by current therapeutic strategies. Due to the slow decay rate of the HIV reservoir, computational data suggest that it might take up to 70 years on ART to completely eradicate the infection [5, 6]. Latency Reversing Agents (LRAs) have been identified and used to induce proviral transcription in latently infected cells [7,8,9,10] with subsequent expression of viral antigens on the cell surface that can be targeted by HIV-1-specific antibodies (Abs)
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