Abstract
HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42–45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38–40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.
Highlights
Fever is a physiological process induced by endogenous pyretics (IL-6, IL-1b, Tumor Necrosis Factor a (TNFa)) in response to stresses such as pathogen infection
Enhanced HIV-1 replication in CD4+ T cells grown at 39.5uC We first analyzed the effect of hyperthermia on HIV-1 replication in Jurkat lymphoid cells and in primary CD4+ T lymphocytes
Hyperthermia is known to enhance the functions of immune cells and to confer protection against pathogen infection [1], [2], [4], [5], Previous studies on temperature and HIV-1 mostly focused on chronically infected cell lines [31], [32] or used non-physiological heat shock treatment to study viral reactivation from latency
Summary
Fever is a physiological process induced by endogenous pyretics (IL-6, IL-1b, TNFa) in response to stresses such as pathogen infection. It consists in hyperthermia, an elevation of the body temperature to 38–40uC, associated with an inflammatory state. Hyperthermia increases dendritic cells (DC) maturation, migration and antigen presentation [1]. Hyperthermia intensifies cytotoxic activity of Natural Killer cells and phagocytosis by macrophages [4], [5]. Together, these events explain why fever is often associated with better disease outcome [2]
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