[Early phase of HHV6 infection: role of IE1 and IE2 proteins]. / La phase très précoce de l'infection par le sixième herpèsvirus humain: rôle des protéines IE1 et IE2.

Human herpesvirus 6 (HHV6) is an opportunistic pathogen whose infection or reactivation is associated with diseases such as roseola, central nervous system disorders and organ transplant anomalies. Following its entry into the host cell, the virus utilizes the cellular machinery in order to transcribe its genes and insure the replicative cycle progression. HHV-6 can also latently persist in its host. Immediate-early proteins are rapidly expressed upon cell infection. In particular, IE1 and IE2 proteins play an important role in the establishment of infection. IE1 inhibits interferon-b transcription and may participate in the PML nuclear body aggregation induced by the viral infection. IE2 is a strong transactivator of multiple cell and viral promoters, and contributes to the initiation of the replicative cycle. In this review we have synthesized the current body of knowledge pertaining to the immediate early phase of HHV6 infection, including the role of immediate-early proteins in the replicative cycle and during latency, as well as that of the promoter who regulates their expression.

Human herpesvirus 8 viral FLICE-inhibitory protein inhibits Fas-mediated apoptosis through binding and prevention of procaspase-8 maturation.

Viral FLICE-inhibitory proteins (v-FLIPs) encoded by several herpesviruses and poxviruses share the ability to inhibit apoptosis after engagement of death receptors. In the current article, we provide insights into the mechanisms by which the v-FLIP of human herpesvirus 8 (HHV-8) (also referred to as Kaposi's sarcoma-associated virus) protects cells from apoptosis after Fas-induced signaling. Using v-FLIP expression vectors, our results clearly show that HHV-8 v-FLIP reduces the cleavage of procaspase-8 into its active p18 and p10 protease subunits upon Fas-induced cell death. These results were confirmed by lower caspase-8 and caspase-3 protease activities in extracts of HeLa cells expressing HHV-8 v-FLIP. Coimmunoprecipitation studies further indicate that HHV-8 v-FLIP physically interacts with procaspase-8, but not with Fas-associated protein with death domain in the cellular cytoplasm. These results suggest that binding of HHV-8 v-FLIP to procaspase-8 affects the recruitment and the activation of the latter at the death-induced signaling complex, resulting in diminished apoptotic cascade initiation. Because cellular FLIP was recently reported to modulate promoter containing NF-kappaB motifs and that both HHV-8 and human immunodeficiency virus type 1 (HWV-1) can infect monocytes, we studied the effects of v-FLIP on HIV-1 gene expression. Cotransfection experiments indicated that v-FLIP expression is associated with activation of HIV long terminal repeats: events that were strictly dependent on the presence of NF-kappaB consensus elements. In conclusion, HHV-8 v-FLIP can possibly contribute to the pathogenesis of both HHV-8 and HIV-1 through impaired Fas-dependent killing of infected cells by cytotoxic T cells and through activation of HIV gene expression.

Interleukin-15 as an activator of natural killer cell-mediated antiviral response.

Natural killer (NK) cells are large granular lymphocytes capable of efficient killing of virus-infected and tumor cells in a major histocompatibility complex-independent manner. The cytotoxic killing potential of NK cells can be modulated by a variety of factors, including cytokines such as interleukin-12 (IL-12), IL-15, and interferon (IFN). IL-15 also plays an important role in NK cell development and survival. Killing of virally infected cells by NK cells is likely to represent an important antiviral defense mechanism, especially during the early phase of infection when antigen-specific immunity has yet to be generated. In the present work, we studied the potential of IL-15 to act as a modulator of NK cell-mediated antiviral defense. Our results clearly indicate that IL-15 can curtail infections by 3 human herpesviruses: Herpes simplex virus type 1, Epstein-Barr virus, and human herpesvirus 6. The antiviral activity of IL-15 is dose-, time-, and NK cell-dependent. IL-15-treated NK cells showed an increased killing potential against a variety of cells, including virus-infected target cells. Lastly, using highly purified cell population, we report that IL-15 triggers the synthesis of IFN-gamma from both CD4(+) and NK cells, which can act in both autocrine and paracrine fashion to modulate NK cells cytotoxic potential. In conclusion, IL-15 is a cytokine that can contribute to the establishment of an antiviral state in 2 ways: first by increasing the killing ability of NK cells and second by stimulating the synthesis and secretion of IFN.