Laureate ESCI award for excellence in clinical science 1999: cytokines and the human immunodeficiency virus: from bench to bedside

Replication of the human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), is under the control of both viral and host factors. Among the latter, the regulatory network of cytokines has been shown to affect virtually every step of the virus life cycle, from cell entry to budding of new progeny virions. Proinflammatory cytokines, such as tumour necrosis factor or, can either trigger or potentiate HIV expression via activation of the cellular transcription factor NF-KB. Other molecules, including interleukin 6 (IL-6) and the interferons, can up-regulate HIV expression by acting predominantly at post-transcriptional and/or post-translational levels. Anti-inflammatory cytokines, including transforming growth factor beta, IL-4 and IL-10, counteract these effects but can also potentiate viral replication under different experimental conditions. Chemotactic cytokines (chemokines) have recently entered the arena of host factors controlling viral spreading as potent inhibitors competing with the virus for cell-surface 7-transmembrane domain receptors also acting, together with CD4, as entry co-receptors for HIV. The cytokine network is constitutively activated in most HIV-infected individuals, as demonstrated by recent analysis of intracellular signalling molecules such as the Janus kinase/signal transducer and activator of transcription pathway. Finally, cytokines have already shown their potential use as pharmacological agents able to restore at least some of the compromised immune functions in infected individuals, as exemplified by the potent enhancing effect of IL-2 on the number of circulating CD4(+) T lymphocytes.