Pathogenesis and virulence of herpes simplex virus

Abstract

Two of the most prevalent human viruses worldwide, herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2, respectively), cause a variety of diseases, including cold sores, genital herpes, herpes stromal keratitis, meningitis and encephalitis. The intrinsic, innate and adaptive immune responses are key to control HSV, and the virus has developed mechanisms to evade them. The immune response can also contribute to pathogenesis, as observed in stromal keratitis and encephalitis. The fact that certain individuals are more prone than others to suffer severe disease upon HSV infection can be partially explained by the existence of genetic polymorphisms in humans. Like all herpesviruses, HSV has two replication cycles: lytic and latent. During lytic replication HSV produces infectious viral particles to infect other cells and organisms, while during latency there is limited gene expression and lack of infectious virus particles. HSV establishes latency in neurons and can cause disease both during primary infection and upon reactivation. The mechanisms leading to latency and reactivation and which are the viral and host factors controlling these processes are not completely understood. Here we review the HSV life cycle, the interaction of HSV with the immune system and three of the best-studied pathologies: Herpes stromal keratitis, herpes simplex encephalitis and genital herpes. We also discuss the potential association between HSV-1 infection and Alzheimer's disease.

Keywords: Herpes simplex virus; genital herpes; herpes and Alzheimer’s disease; herpes simplex encephalitis; herpes stromal keratitis; pathogenesis; virulence.

Figure 1.

The HSV virion. The linear double stranded DNA forms the core of the virion and is protected by the icosahedral capsid. The tegument, composed of many viral and cellular proteins surrounds the capsid and connects it with the envelope, where the viral glycoproteins and other membrane associated proteins are embedded

Figure 2.

HSV cell cycle. (1) HSV glycoprotein D or B interact with specific cellular receptors leading to fusion at the plasma membrane (2) of following endocytosis (not shown in this figure). Upon fusion, the capsid is released to the cytoplasm with some attached tegument proteins, while other tegument proteins like VP16 separate from the capsid. (3) The capsid travels to the cell nucleus using microtubuli due to the interaction between UL36 and motor proteins. The linear DNA enters the nucleus . (4) The tegument protein VP16 enters the nucleus together with HCF-1 and Oct-1 and starts transcription of IE genes. (5) The IE genes are translated and participate in the transcription of E genes (6), which take part in the replication of the viral genome (8). Once there are sufficient copies of viral genomes, the products of the L genes facilitate DNA encapsidation (11). The mature, DNA containing capsids (C capsids) leave the nucleus through an envelopment-deenvelopment process and acquire tegument and envelope (not shown) prior to cellular egress (14)

Figure 3.

Initial steps of HSV primary infection. During primary infection, HSV infects epithelial cells in the mucosa or skin. Infection of the skin requires rupture of the keratin layer composed of dead cells. The virus replicates lytically in epithelial cells producing new infectious viral particles that reach nerve endings of peripheral neurons, where HSV establishes latency

Figure 4.

Establishment of HSV latency in neurons. Following entry in the neurite end the capsid containing pUL36 and other inner tegument proteins travel to the nucleus independently of other tegument proteins like VP16. The transport of VP16 is not efficient and it probably reaches the nucleus later than the viral DNA. This, together with other factors, leads to the deposition of histone H3 and subsequently the addition of constitutive and facultative heterochromatic marks (H3K9me3 and H3K27me3, respectively) on most viral promoters, repressing their transcription. On the contrary, the LAT locus contains facultative heterochromatin and euchromatin marks (H3K4me3 and H3K9/14acetyl), facilitating its transcription