The goal of this project is to understand reservoir effects and curative potential of a promising CCR5-depleting bispecific antibody (bsAb) given with days of ART initiation to infants with either limited or robust pre-ART viral replication. The agent is a bsAb with one arm directed against CD3 and the other against CCR5, which approximates cytotoxic T cells to CCR5-expressing cells. These cells form a key part of the HIV reservoir in ART-treated people and have been eliminated in notable cases of HIV cure. Our preclinical studies revealed >50% remission in simian immunodeficiency virus (SIV)-infected infant animals after bsAb treatment. We hypothesize that these effects were achieved through a combination of true reservoir depletion and removal of SIV target cells required for rebound. In this R01 application, we propose to improve the manufacturing and safety of this bispecific antibody and then rigorously test the two proposed mechanisms of action. We will screen early-infected infants to identify those with either (i) limited viral replication and the potential for cure, or (ii) robust replication and likelihood of establishing measurable reservoirs that can be followed during and after bsAb treatment. These two groups will be separately studied in order to isolate and measure reservoir effects and the potential for cure. Hypothesis: Highly purified CD3/CCR5 bsAb, given within days of ART initiation, safely achieves significant SIV reservoir depletion from infants, which is sufficient to induce durable remission in those with restricted reservoirs or can act synergistically with bnAb to achieve remission in animals with larger reservoirs. Aim 1. Test CCR5 depletion and side effects caused by CD3/CCR5 bsAb produced as a CrossMab, compared to controlled Fab-arm exchange (cFAE). Aim 2. Demonstrate the potential for infant SIV cure via CCR5 depletion near the time of ART initiation, when viral replication and reservoirs are limited. Aim 3. Measure the interference with reservoir establishment that is achievable by CCR5 depletion, bnAb, or the two combined in early-treated infants with robust viral replication.