To target the HIV CD4i envelope epitope, we primed rhesus macaques with replicating Ad-rhFLSC (HIV-1BaLgp120 linked to macaque CD4 D1 and D2), with or without Ad-SIVgag and Ad-SIVnef. Macaques were boosted with rhFLSC protein. Memory T-cells in PBMC, bronchoalveolar lavage and rectal tissue, antibodies with neutralizing and ADCC activity, and Env-specific secretory IgA in rectal secretions were elicited. Although protective neutralizing antibody levels were induced, SHIVSF162P4 acquisition following rectal challenge was not prevented. Rapid declines in serum ADCC activity, Env-specific memory B cells in PBMC and bone marrow, and systemic and mucosal memory T cells were observed immediately post-challenge together with delayed anamnestic responses. Innate immune signaling resulting from persisting Ad replication and the TLR-4 booster adjuvant may have been in conflict and reoriented adaptive immunity. A different adjuvant paired with replicating Ad, or a longer post-prime interval allowing vector clearance before boosting might foster persistent T- and B-cell memory.