The demonstration that high levels of viral replication occur from the onset of infection and throughout the course of the disease has affected significantly not only the understanding of the pathogenic mechanisms but, also, therapeutic strategies. Indeed, with the availability of several new HIV-specific drugs, early intervention is becoming widely accepted. Moreover, as virus disseminates into the infected host, it establishes reservoirs which allow the virus to escape the immune system and to persist. These reservoirs include lymphoid and non-lymphoid organs (lymph nodes and reproductive system and brain, respectively), but also resting T cells. In this research plan, the Principal Investigator proposes to identify therapeutic strategies that will lead not only to a decrease of HIV to unquantifiable levels in circulation but, also, to reduce total body viral load in longer-lived reservoirs and affect second and third phase decay kinetics. Ideally, this strategy will also prevent the destruction of the immune system that begins at the earliest stage of primary HIV infection. State-of-the-art methodologies will be used to assess the baseline viral load in the periphery and in the different reservoirs, including lymphoid and non-lymphoid organs, and T cells. The cellular immune response, as measured by the T-cell receptor repertoire and the presence of effector CTLs, will also be assessed. Then, within the context of a clinical trial comparing two aggressive anti-retroviral treatment modalities, the researchers will measure the virologic and immunologic response to therapy in 120 patients recruited over a period of one year. The modalities will include a nucleoside reverse transcriptase and a protein inhibitor, together with or without a non-nucleosidic RT inhibitor. After six months, a subgroup of 20 patients with the best responses to treatment will be randomized (1:1 basis) to receive an immunologic intervention (IL-2) designed to mobilize any remaining latent tissue virus stores, in an effort to enhance the effects of therapy. The latter will be measured by the ability to contain viral replication in all tissue stores (including lymph tissue and genital fluids) as well as the ability to restore immune function. The information gathered will be interpreted in the context of a formal evaluation of drug compliance, the theoretical framework for which will be integrated into the conduct of the study. Altogether, this therapeutic intervention will allow the researchers to determine the kinetics of dissemination of virus in latent stores and to verify the capacity of early intervention to prevent the establishment of these reservoirs and, hence, to favor removal of virus from those compartments which interfere with the physician's capacity to eliminate the virus.
