Highly active antiretroviral therapy has made a significant impact on the natural history of human immunodeficiency virus type 1 (HIV-1) infection. A nearly uniformly fatal infection has been transformed into one that is treatable and chronic when managed properly, particularly in resource-abundant settings (42). Treatment regimens have evolved, with less toxicity in the short and long term, as has compactness, accompanying improved ease of administration. At the same time, new agents directed against established and new targets, both viral and cellular, are on the therapeutic horizon.Despite this apparent success over the past decade, we are still left with a treatment paradigm of lifelong antiviral therapy for the majority of HIV-1-infected individuals. Concerns regarding current therapies include high cost (5), emergence of drug resistance in the face of less than perfect adherence (4), cardiovascular complications due to hyperlipidemia (12, 13), metabolic complications due to hyperglycemia and insulin resistance (9, 17, 31), the possibility of renal disease with chronic use of nucleotide reverse transcriptase inhibitors (44), and perhaps persistent low-level viral replication during therapy (20,56). For all of these reasons, we and others have attempted to pilot alternative treatment paradigms-antiviral therapy for finite periods of time with therapeutic vaccination, followed by treatment termination or structured treatment interruptions (32,33,40). Such efforts have not resulted in sustained control of viral replication in vivo in most of the participants in these studies; nevertheless, despite "failure," lessons have been learned. One striking observation in our treatment interruption studies in patients treated during acute and early infection was that after viral rebound, a spontaneous reduction in HIV-1 RNA levels in plasma was observed, 1.7 log 10 units on average (range, 0.3 to 3.1) (33). This is comparable to what is seen with potent antiviral agents and we believe is likely due to an anamnestic immune response in an already primed patient with an intact, inducible immune system. Given these findings, we hypothesized that if we could complement the autologous cellular immune response induced by virologic rebound with a neutralizing serologic response obtained with infusions of potent neutralizing monoclonal antibodies (MAbs), perhaps sustained virological remission could be achieved. Three such MAbs were made available for clinical use: 2G12, which binds to a carbohydrate moiety on the silent face of gp120 (54), and 4E10 and 2F5, both of which bind to