HIV: master of the host cell

Abstract

The human immunodeficiency virus has evolved various mechanisms to exploit its host cells, including the interruption and augmentation of signal transduction pathways. Recently, two DNA microarray studies have illustrated a remarkably broad-based perturbation in host transcriptional responses, which is in part mediated by the HIV-encoded Nef protein. HIV therefore seems to function as a 'master regulator' of cellular gene expression.

Figure 1

Modulation of the gene responses of host T cells by HIV. (a) Expression of Nef in T cells results in the induction of numerous viral permissivity factors as well as genes associated with T-cell activation. The induction of secreted factors, such as IL-4 and TGF-β, may generate secondary signals that favor viral replication, while the up-regulation of chemokines such as MIP-1α and MIP-1β may attract cells to the site of infection, perhaps aiding transmission of the virus. Although the precise mechanisms through which Nef modulates signaling have not been elucidated, it has been implicated in exerting controls on a number of membrane-proximal pathways. (b) Infection of T cells with intact HIV induces gene responses that are more complex and include the up-regulation and suppression of functionally diverse host genes. As infection proceeds, host-cell genes are increasingly suppressed, and there is a shift toward the induction of factors associated with a cytopathic response, including those regulating apoptosis and responses to genotoxic stress. The anti-viral gene IFN-α is induced relatively early in infection, and may modulate a variety of response cascades. HIV may elicit these transcriptional changes through a wide variety of mechanisms, either directly (though viral factors such as Nef, Env, and Tat), or indirectly, by inducing cellular stress during the acute phase of infection. Other factors included in the figure are discussed elsewhere in the text.