PROJECT SUMMARY One strategy for eradicating the HIV-1 viral reservoir combines a means of activating viral gene expression in latently infected T cells (a ‘kick’) with a way to eliminate these activated cells (a ‘kill’). The TLR7 agonist GS-9620 is a safe, well tolerated latency reversing agent that indirectly induces latently infected T cells to produce virus. Preliminary data indicates that it can partially reduce, or in some cases perhaps completely eliminate, the SIV reservoir in rhesus macaques. eCD4-Ig is an antibody- like entry inhibitor with unmatched breadth and very potent neutralizing and antibody-dependent cell- mediated cytotoxicity (ADCC) activities against HIV-1, HIV-2 and SIV. Moreover, it can protect macaques against from repeated high-dose challenges with two divergent viruses – SIVmac239 and SHIV-AD8. Finally a single dose of an IgG1 form of human eCD4-Ig protein can suppress infection in macaques by 2.5 logs without evidence of viral escape. eCD4-Ig’s potent neutralization and ADCC activities, and its exceptional breadth, suggest that it may uniquely overcome the diversity of the viral reservoir and facilitate the elimination of most reactivated cells. Accordingly, we will test the hypothesis that the effector functions of eCD4-Ig can accelerate reduction of the latent reservoir observed in GS-9620-treated macaques. To do so, we will first optimize the half- life, immunogenicity, neutralization potency, and ADCC activities of eCD4-Ig. We will then optimize the schedule, dosing, and route of administration of GS-9620, and establish the relationship between GS- 9620-induced virus ‘blips’ and reservoir reduction. Finally, we will compare GS-9620, eCD4-Ig, and both therapies combined, for their abilities to reduce the size of the latent reservoir and/or establish a stable state of virologic control. If successful, these studies will lay a foundation for future human clinical trials combining GS-9620 and eCD4-Ig.