Principles of Virology, Volume 2. S. Jane Flint

      Sexual activity can result in tears or abrasions in the vaginal epithelium or the urethra, allowing virus particles to enter. Some viruses infect the epithelium and produce local lesions (for example, human papillomaviruses, which cause genital warts). Others penetrate deeper, gaining access to cells in the underlying tissues and infecting cells of the immune system (human immunodeficiency virus type 1) or the peripheral nervous system (herpes simplex virus type 2). Infection by the latter two viruses invariably spreads from the initial urogenital site to other tissues in the host, thereby establishing lifelong infections. Viral vaginitis (inflammation within the vaginal canal) can result from infection by herpes simplex virus type 2. This infection often causes painful lesions or sores, often visible on the vulva or the vagina, but occasionally found deeper in the vaginal canal. Because herpesviruses cannot be cleared from infected hosts, recrudescence can occur following stress, natural changes in the thickness of the canal during the menstrual cycle, or other infections. Herpes vaginitis could also affect the mouth and pharynx if oral sex is performed during a period in which virions are actively shed.

      Viruses that gain entry by the urogenital tract are extremely common. Approximately one in six people between 15 and 50 years of age has genital herpes, and as this is a lifelong infection, the risk of transmission to sex partners is high. Herpesvirus infection is often asymptomatic, although the virus can still be shed and infect others. In pregnancy, infections by these viruses pose a particular risk to the developing fetus and can result in miscarriage, early delivery, or lifelong infection that begins in the neonate, dangers that can be mitigated by Caesarian delivery. Moreover, transmission of human papillomaviruses can result in genital warts and cervical cancer. Such viruses have a high transmissibility rate: there is a >20% chance that an uninfected individual will pick up the virus from an infected partner over a 6-month period. It is sobering to note that individuals may be affected by multiple sexually transmitted pathogens, and a preexisting infection with one may predispose to infection with another. For example, a genital herpes lesion provides an excellent portal for human immunodeficiency virus type 1.

      Human semen is a particularly robust carrier of viruses: it is estimated that up to 27 distinct viruses can reproduce in, and be spread by, semen. These include viruses that are well known to be sexually transmitted, including human immunodeficiency virus type 1 and herpes simplex type 2, but also include emerging pathogens such as Ebola virus and Zika virus. Viruses such as influenza, dengue, and severe acute respiratory syndrome virus have been found in the testes, though it is not known if these viruses can be sexually transmitted. Even if these viruses are not sexually transmitted, their presence may nevertheless affect fertility, or increase the risk of acquiring a sexually transmitted disease. Some of these viruses, including the papillomaviruses, may even cause mutations in the DNA of sperm, which could then fertilize an egg and pass along the virus-induced mutations to future generations.

Placenta

      A primary route by which a virus can be vertically transmitted from mother to offspring is to cross the placenta. Thus, in pregnant females, viremia may result in infection of the developing fetus. Maternal immune cells do not traverse the placental barrier, though these immune cells could bring virus into proximity with the placenta. Transplacental infections are distinct from perinatal infections, in which the virus is acquired via contact with maternal blood as the baby is delivered through the birth canal.

      While some perinatal infections can be avoided by Caesarian delivery, in utero infections cannot. Historically, the primary transplacental viral infections of concern were rubella, cytomegalovirus, and herpes simplex virus. These viruses, along with the parasite Toxoplasma, comprised the four pathogens once defined by the acronym TORCH. Infection by any of these pathogens poses a substantial threat to the fetus. For example, the risk of fetal infection in mothers who are infected with rubella virus during the first trimester is approximately 80%. Similarly, intrauterine transmission of human cytomegalovirus occurs in approximately 40% of pregnant women with primary infection.

The recent Zika virus outbreak and appearance of birth defects in children born following in utero infection focused greater attention on transplacental virus infections (Fig. 2.10). The placenta is the sole barrier and conduit between the maternal and fetal blood supply and is responsible for gas, waste, and nutrient exchange throughout pregnancy, and its morphology and constitution change throughout pregnancy. Syncytiotrophoblasts lie at the maternal-fetal blood interface and are in direct contact with maternal blood; they are therefore crucial for protecting the fetus from circulating pathogens. Indeed, the syncytiotrophoblast layer is highly resistant to viral infections, including by teratogenic viruses such as rubella, cytomegalovirus, and Zika virus. The mechanisms by which teratogenic viruses cross the placenta are largely unknown, and there may be multiple mechanisms of trans mission to the fetus. Some pathways that have been proposed to allow for viral vertical transmission include traversing the syncytiotrophoblast layer by antibody-dependent transcytosis, increased tropism for placental cell types that are more permissive to virus infections, and maternal immune-mediated damage to the syncytiotrophoblast layer, thus allowing for breaches in the placental barrier. Alternatively, herpes simplex virus may spread from the ascending intravaginal route to infect the fetus, thereby bypassing the syncytiotrophoblast layer altogether.

Figure 2.10 Transplacental virus infections. Several viruses, including Zika virus, rubella virus, cytomegalovirus, and herpes simplex virus, can cross from mother to fetus. How these vertically transmitted infections might occur is dependent on multiple variables including virus type and fetal age. Syncytiotrophoblasts are crucial cells that lie at the maternal-fetal interface and are resistant to infection by many viruses. Routes of vertical transmission across the placenta could include breaks in the syncytial cell layer, targeting other cell types such as cytotrophoblasts or extravillous trophoblasts, or bypassing this by mechanisms such as direct antibody-mediated transcytosis.

Although the portals described above are all anatomical “gateways” by which viruses (and other pathogens) may cross barriers to initiate an infection, human cognition and intuition may also influence the viral pathogens to which we may be exposed (Box 2.6).

Viral Tropism

      The previous sections discuss viral access to particular tissues, and entry points into the host. But there is more to initiating an infection than just access. Before describing how viruses move throughout an infected host, it will be useful to discuss briefly the concept of viral tropism: the cellular and anatomical parameters that define the cells in which a virus can reproduce in vivo. Most viruses are restricted to specific cell types in certain organs. Tropism is governed by at least four parameters. First, in order for a virus to infect a cell, the cell must be susceptible; that is, it must have receptors that the virus binds to allow entry. However, expression of an entry receptor and translocation into the cytoplasm is not sufficient to ensure virus reproduction. Successful production of viral progeny depends on cellular gene products (or other cellular components) to complete the infectious cycle, which may be synthesized by some cell types but not others. The presence of such proteins and molecules renders the cell permissive to completion of the virus reproduction cycle and release of infectious virus particles. Although a cell may be both susceptible and permissive, infection may not occur because virus particles are physically prevented from interacting with the tissue; thus, the host cells must be accessible to virus. Finally, an infection may not progress, even when the tissue is accessible and the cells are susceptible and permissive, because of intrinsic and innate immune defenses that resolve the infection before spread can occur.

BOX 2.6

      DISCUSSION