HIV REPLICATION IN IL-2-STIMULATED PERIPHERAL-BLOOD MONONUCLEAR-CELLSIS DRIVEN IN AN AUTOCRINE PARACRINE MANNER BY ENDOGENOUS CYTOKINES

Replication of HIV is regulated by virus-encoded regulatory proteins, as well as by a variety of cellular factors including cytokines. In th e present study, we have investigated the autocrine/paracrine effects of endogenous cytokines on HIV replication in primary PBMCs of healthy HIV seronegative individuals. Addition of rIL-2 to cultures between 0 and 72 h after isolation of PBMCs allowed the replication of primary HIV isolates and laboratory-adapted HIV strains to levels comparable w ith or greater than those obtained in parallel cultures of autologous PHA-blasts. In this regard, both major cellular targets of HIV infecti on, CD4(+) T lymphocytes and mononuclear phagocytes, were maintained f or several weeks in IL-2-stimulated PBMC cultures and virion productio n was observed in both cell lineages. The kinetics of secretion of sev eral cytokines (such as TNF-alpha, IL-1 beta, IL-6, and IFN-gamma), as well as expression of cellular activation markers, paralleled HIV rep lication in IL-2-stimulated PBMCs. Endogenous pro-inflammatory cytokin es and IFN-gamma played a major role in the regulation of HIV replicat ion in IL-2-stimulated PBMCs, as determined by the ability of several anti-cytokine Abs or antagonists to suppress HIV production; this was not the case in parallel cultures of autologous PHA-blasts. Thus, IL-2 -stimulated PBMCs may represent a more physiologic in vitro system tha n PHA-blasts for the study of HIV infection and replication, and shoul d prove useful in investigating the role of cytokines and other host f actors in the regulation of HIV production.