Overview of primary HHV-8 infection

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1 Overview of primary HHV-8 infection HHV-8, also known as Kaposi sarcoma-associated herpesvirus (KSHV), is a gamma herpesvirus primarily transmitted through saliva. The virus initially replicates in epithelial s of the oropharynx and subsequently targets B s which is a primary viral reservoir. Infection of B s usually results in viral latency characterised by minimal viral gene expression. Hence these s are not readily detectable by immune surveillance. Trafficking of infected B s to lymphoid tissues allows additional B s to be infected when the lytic replication is triggered. Latently infected B s can disseminate to other parts of the body via the blood. HHV-8 also has the ability to infect endothelial s potentially causing a malignancy to develop. Lytic infection of B s in the oropharynx may promote infection of epithelial s and shedding of virus into saliva for potential transmission to other hosts. Latently infected B s remain undetected in the body for long periods of time and the virus is therefore present lifelong. HHV-8 infection is usually asymptomatic when the immune system is intact. HHV-8 Infection Transmission Lymphoid tissue Oropharynx Virus shedding Lytic infection B Reactivation Epithelial s Recirculation Mucosal lymphoid tissue Dissemination Blood Infected B Latent inection B

2 HHV-8 Normal control of HHV-8 infection Spindle HHV-8 receptor (eg. heparan sulfate, α3β1 integrin, DC-SIGN, xct, epha2) B Infected B Viral episomes Cell death Recirculation Replication Latent infection B Minimal viral genes expressed during latency Kaposin vflip vcyclin LANA vil-6 K1 RTA Reactivation Lytic infection B KILL Natural killer (NK) Immune evasion CD8+ cytotoxic T (CTL) Natural killer T (NKT) HHV-8 can use a variety of receptors to gain entry into target s that are primarily B s but also epithelial and endothelial s. The majority of B s are latently infected and contain episomal copies of viral DNA in the nucleus which expresses a minimal number of viral genes needed to maintain the viral episomes and prevent activation of the lytic. The lytic is activated by external events such as immune activation of the B via BCR stimulation or interaction with CD4+ helper T s. Latent viral proteins inhibit the activation of the B, however, periodic reactivation of infected B s does occur to promote transmission to other hosts. Additional genes transcribed during lytic replication also interfere with anti-viral immunity involving both innate and adaptive responses.

3 Epidermis HHV-8 infection of endothelial s Langerhans Keratinocyte Dermis Skin capillary venule Circulating endothelial stem A common manifestation of HHV-8 infection, when the immune system is compromised, is the development of malignant lesions in the skin, although involvement of mucosal or visceral sites are also possible. It is thought that these lesions develop when vascular endothelial s in skin capillaries become infected with HHV-8. This may occur by direct infection of capillary endothelial s or via recruitment of circulating infected endothelial progenitor s to the vasculature. In immunocompetent individuals, HHV-8 infection is usually asymptomatic, since virus replication is controlled. The virus escapes detection by existing in latent form, however, if HIV infection occurs or immunosuppressive therapy is introduced, reactivation of latent virus is increased leading to increased infection of endothelial s.

4 Epidermis Transformation of HHV-8 infected endothelial s Langerhans Keratinocyte Dermis Transformation and proliferation VEGF gp130 VEGFR Spindle formation Lytic infection of endothelial vil-6 Sub-endothelial tissue invasion vgpcr Skin capillary venule Infection of endothelial s leads to their transformation and proliferation. Invasion of the subendothelial layer, such as the dermis of the skin, occurs. Proliferation is mainly driven by cytokine stimulation of latently infected s in a paracrine manner. Viral cytokines such as vil-6, a homologue molecule of human IL-6, stimulates the production of VEGF. Viral IL-6, produced by latent and lytically infected s, is able to stimulate the gp130 chain of the IL-6 receptor and results in modulation of gene transcription. The viral GPCR, a constitutively active homologue of the IL-8 receptor, is expressed in lytically infected s and also alters intraular signaling pathways to promote transformation and cytokine production. The secretion of VEGF is a primary driver of endothelial proliferation via the VEGF receptor. Most of the proliferating s are latently infected with HHV-8 and develop into characteristic spindle s.

5 Epidermis Proliferation of HHV-8 infected spindle s Langerhans Keratinocyte Dermis Kaposi sarcoma formation Angiogenesis Lytic infection of spindle vgpcr vccl1 vccl3 vccl2 VEGFR VEGF IL-6 IL-8 Skin capillary Immune venule recruitment T-s Macrophages VEGF gp130 The formation of a Kaposi sarcoma lesion is due to the increased proliferation of latentlly infected spindle s. This is driven by low levels of HHV-8 lytic replication in some s resulting in the production of cytokines, particularly VEGF and vil-6. VEGF promotes additional angiogenesis that supplies oxygen and nutrients to the tumour s. Increased vascularisation and trapping of extravasated red s in spaces between the spindle s leads to the characteristic red colour of the lesions. Inflitration of immune s such as T s, plasma s and macrophages, is also a consequence of chemokine release from lytic infected s. Viral chemokines that are homologues of human CCL1,-2 and -3 contribute to the chemotaxis of immune s to the site of the lesion. vil-6

6 HHV-8 dissemination and development of lesions Spindle Kaposi sarcoma lesion Lytic viral replication HHV-8 infected circulating endothelial stem HHV-8 virions Kaposi sarcoma lesions develop in the skin at late stages of HHV-8 reactivation following a failing of the immune system to control virus replication. Dissemination of virus produced by increased lytic replication promotes the development of additional lesions which may also be due to increased infection of circulating endothelial stem s. Malignancies can also develop at mucosal sites or in other organs. Spindle s do not appear to metastasise to other sites, rather new lesions develop following free virus infections of endothelial s or recruitment of infected endothelial s to the vasculature.