Vaccines for Latent Viral Infections

Some viruses are able to escape the immune responses generated against them and to establish a latent state that is not visible to the immune system. Such viruses hide in CD4+ T cells, all T cells, B lymphocytes, germinal epithelial cells, neurons and others. They can reactivate at times when the immunity is compromised. It is not known what are the effects, if any, of dormant viruses on the immune system. Some of these viruses contribute to malignant transformation of cells. Recent studies have implicated that presence of latent viruses such as CMV might be driving the T cells to terminal differentiation and exhaustion. Retroviruses incorporate into the human genome and now represent as much as 8% of it constituting of about 30 000 different retroviruses. In addition, various other transposable elements like these make up to 45% of the human genome. Other latent viruses such as Bornavirus are believed to be involved in the pathogenesis of human psychiatric diseases such as bipolar disorder and depression. Attempts to design vaccines that will prevent the virus from going into latency have been scarce.

In latent infections, overt disease is not produced, but the virus is not eradicated. The virus may exist in a truly latent noninfectious occult form, possibly as an integrated genome or an episomal agent, or as an infectious and continuously replicating agent, termed as a persistent chronic viral infection. Reactivation of a latent infection may be triggered by various stimuli, including changes in cell physiology, super-infection by another virus, and physical stress or trauma. Viruses that cause latent infections can persist at the same time in different cell types of one or more tissues or organs. This review summarizes the characteristics and mechanisms by which persistent infections are maintained by modulation of both virus and cellular gene expression and modification of the host immune response.

Herpes simplex viruses belong to the subfamily Alphaherpesvirinae and the genus Simplexvirus and have the capacity to establish latent infections in sensory ganglia of humans. Intermittent reactivation of the virus can cause retrograde transportation to the dermatome where initial infection occurred, the virus crosses into the stratified squamous epithelium where it starts replicating again. Herpes simplex viruses that cause infections in humans are HSV-1 (infection of the skin and oral mucosa) and HSV-2 (sexually transmitted infection of the genital tract). Despite almost a century old efforts to develop vaccine against HSV viral infection, results from clinical trials in humans have been disappointing. Three main approaches were used to develop the vaccine: glycoprotein vaccine (gB and gD), mutated inactivated live virus and DNA vaccines. Although all vaccine candidates showed excellent results in animal models, significant protection was not seen in human clinical trials. This not only questions the validity of the animal models but also calls for a change in the current strategies in designing future vaccine candidates.

In designing the vaccine candidates very little attention was devoted to the immune evasion mechanisms of the virus that are the main reason that the virus is able to persist and to reactivate when immune responses weaken.

Cytomegalovirus (CMV) is found throughout the world in all geographic and socioeconomic groups, but, in general, it is more widespread in developing countries and in areas of lower socioeconomic conditions. CMV still remains a major human pathogen causing significant morbidity and mortality in immunosuppressed or immunocompromized individuals. Between 50% and 80% of adults in the United States are infected with CMV by 40 years of age. CMV is the most common congenitally transmitted virus, resulting in approximately 1 in 150 children born with congenital CMV infection, and in approximately 1 in 750 children developing permanent disabilities due to CMV. Thus, development of vaccines against CMV infections has been a major biomedical research priority. In this chapter, immunobiology of host- CMV interactions is discussed as related to the host immune responses against viral infection, providing insights into the complex interplay between host and virus that facilitates viral persistence. In addition, an update on CMV vaccines that are currently in preclinical and clinical development, is provided, outlining important questions about the nature of protective immune responses that will be required for potential CMV immunization strategies.

Varicella Zoster Virus (VZV) causes a highly contagious infection, chicken pox and has the capacity to cause latent persistent infection of the dorsal root ganglia. The latent virus can reemerge inducing painful blistering of the skin called herpes zoster or shingles. Worldwide varicella immunization with an attenuated OKA/Merck VZV considerably reduced the incidence of the disease but did not prevent latency. Introduction of a second dose of the vaccine and the vaccine for people over 50, Zostavax, consisting of a much larger dose of the same vaccine virus, reduced the incidence of chicken pox but did not prevent latency and reemergence of the virus as herpes zoster. This review provides an overview of the structure of the virus, mechanism of infection and known evasion mechanisms that VZV uses to establish latency and persistence.

Epstein-Barr virus (EBV) infection is associated with a spectrum of fatal diseases including Burkitt’s lymphoma (BL) and nasopharyngeal carcinoma (NPC). Higher incidence of BL and NPC seen in developing world demands an effective vaccine to prevent infection and disease onset. EBV primarily infects people during infant or adolescent ages and establishes latent infection. Vast majority of EBVassociated diseases develop later in immune-compromised individuals, suggesting the link between host immunity and viral reactivation. This chapter discusses viral factors that EBV produces whose interactions with host may determine infection, reactivation, immune evasion and disease progression, and further reviews vaccine formulations tested to date. Knowledge in such viral factors is indispensable for vaccine advances.

Human Immunodeficiency Virus (HIV) is a retrovirus that establishes latent infection in humans. The latency period varies in duration but eventually ends in depletion of CD4+ T lymphocytes, secondary immunodeficiency and death from opportunistic infections. The virus is a RNA virus with envelope and glycoprotein spikes protruding from it. The envelope glycoprotein plays an essential role in viral entry into the host cell. In addition, it is an important factor in the capacity of the virus to escape the immune system forming the so called ‘glucan shield’ that protects the virus from destruction. Both dendritic cells and B cells can carry the infectious virus on their surface as they travel to T lymphocyte rich lymphoid organs and spread the infection through their interaction with T cells. HIV has caused a worldwide epidemic that is currently kept under control with retroviral therapy in the developed world but has devastated large portion of the African continent. Tremendous efforts were put forward by the world research community to develop vaccine against HIV that resulted in moderate to poor protective efficacy of vaccine candidates.

With new evidence emerging that viral latent infections might have yet unknown negative effects, it is becoming a necessity to look into the factors that allow these viruses to persist and establish latency. Designing vaccines that will prevent the initial infection and establishment of latency should become the main focus. To succeed in such a goal is not impossible but requires major refocusing of the research efforts. The viral escape mechanisms that are used during the initial stages of the acute primary infection should be carefully examined and fully understood. Once this is accomplished, developing strategies that will disarm these escape mechanisms and allow the immune system to clear the virus should become an achievable goal.