HIV (human immunodeficiency virus) is a human retrovirus with a total of 40 million people living with HIV (PLWH) globally as of 2023.  While HIV is relatively well controlled with current antiretroviral therapies (ART), 630,000 PLWH died in 2023 from AIDS related illnesses. Of the 40 million PLWH, 10 million are unable to access ART resulting in unsuppressed viremia and the progression to AIDS. While ART suppresses viral replication, reservoirs of latently infected cells remain invisible to the immune system.  Thus, therapies are still needed to establish a functional cure. We have designed and produced a tri-specific killer engager (TriKE) that engages CD16 on NK cells and utilizes the extracellular domain 1 of human CD4 (CD4 ECD) to engage HIV-1 envelope to direct natural killer (NK) cell killing of infected cells with both components linked by monomeric IL-15. Flow staining of reactivated or an uninfected T-cell line, A3.02 incubated with a His-tagged CD4 ECD TriKE showed binding of the TriKE specifically to reactivated infected cells. Use of the CD4 TriKE in vitro against the reactivated ACH-2 showed a significant enhancement in NK cell degranulation compared to non-reactivated ACH-2 or the uninfected A3.02. Positive in vitro data allowed us to initiate a small animal trial to investigate the TriKE function in vivo. An initial dose escalation trial of CD4 ECD TriKE in uninfected rhesus macaques has demonstrated no dose limiting toxicities with a maximum subcutaneous dose of 300 ug/kg when dosed daily for 1 week. Animals treated with the CD4 ECD TriKE exhibited a strong NK proliferative response in both the peripheral blood and LN. Dosing information will be used to design an infected rhesus macaque model to investigate the ability of the TriKE to contribute as both a latency reversal agent as well as reduce the viral reservoirs.