Principles of Virology, Volume 2. S. Jane Flint

Figure 2.13 Entry, dissemination, and shedding of blood-borne viruses. Shown are the target organs for some viruses that enter at epithelial surfaces and spread via the blood. The sites of virus shedding (red arrows), which may lead to transmission to other hosts, are also shown.

Figure 2.14 The lymphatic system. Lymphocytes flow from the blood into the lymph node through postcapillary venules. Green indicates lymphatics; red indicates the bloodstream. Adapted from Mims CA et al. 1995. Mims' Pathogenesis of Infectious Disease (Academic Press, Orlando, FL), with permission.

      The migratory nature of many immune cells allows viruses that infect these cells to move quickly and clandestinely throughout the host. Because viral components are inside a cell during transport, they are effectively shielded from antibody recognition. Traversing the blood-brain barrier poses a particular challenge for a free virion, as the capillaries that make up this unique barrier limit the access of serum molecules to the brain. However, activated macrophages can pass through, freely de livering viruses such as measles, some enteroviruses, and chikungunya virus into the brain tissue. This process is often referred to as the Trojan Horse approach, because of its similarity to the legend of how the Greeks invaded and captured the protected fortress of Troy. In this legend, the Greeks built a large wooden horse that was disguised as a victory trophy, but instead, many Greek soldiers hid within the hollow horse. Once the “gif horse” was safely inside the city walls, the soldiers emerged and quickly achieved victory.

The term viremia describes the presence of infectious virus particles in the blood. Active viremia is a consequence of reproduction in the host, whereas passive viremia results when particles are introduced into the blood without viral reproduction at the site of entry (as when an infected mosquito inoculates a susceptible host with West Nile virus). The release of progeny virus particles into the blood after initial reproduction at the site of entry constitutes the primary viremia phase. The concentration of particles during this early stage of infection is usually low. However, subsequent dissemination of the virus to other sites results in the release of considerably more virus particles. The delayed accumulation of a high concentration of infectious virus in the blood is termed secondary viremia (Fig. 2.15). The two phases of viremia were first described in classic studies of mousepox (Fig. 2.1).

Figure 2.15 Generic characteristics of viremia. Passive viremia occurs when the host is the recipient of infectious virus from an exogenous source (e.g., an infected mosquito). Soon thereafter, a modest primary viremia can occur as a result of virus reproduction at the site of entry. Virus then can be detected in blood, perfusing tissues such as muscle, spleen, and blood vessels. Following reproduction in these sites, a much more robust infection can be detected in the blood, which then can lead to infection of susceptible cells in other organs. Adapted from Nathanson N (ed). 2007. Viral Pathogenesis and Immunity (Academic Press, London, United Kingdom), with permission.

The concentration of virus particles in blood is determined by the rate of their synthesis in permissive tissues and by how quickly they are released into, and removed from, the blood. Circulating particles are engulfed and destroyed by phagocytic cells of the reticuloendothelial system in the liver, lungs, spleen, and lymph nodes. When serum antibodies appear, virus particles in the blood may be bound by them and neutralized (Chapter 4). Formation of a complex of antibodies and virus particles facilitates uptake by Fc receptors carried by macrophages lining the circulatory vessels. These virus-antibody complexes can be sequestered in significant quantities in the kidneys, spleen, and liver, prior to elimination from the host via urine or feces. On average, individual virus particles may remain in the blood from 1 to 60 min, depending on parameters such as the physiology of the host (e.g., age and health) and the size and structural integrity of the virus particles. Some viral infections are noteworthy for the long-lasting presence of infectious particles in the blood. Humans infected with hepatitis B and C viruses or mice infected with lymphocytic choriomeningitis virus may have active viremia that persists for months to years. In some cases, movement to the kidney and liver is aided by engagement of virus particles by scavenger receptors found on circulating and resident macrophages. Such receptors bind to common ligands on pathogens, such as lipoproteins, apoptosing cells, cholesterol, and carbohydrates, removing them from the blood. For example, the resident macrophages of the liver, kupffer cells, express high levels of the scavenger receptor type A, which binds to adenovirus particles, targeting them for degradation and elimination from the infected host.

      Viremia is of diagnostic value to monitor the course of infection in an individual over time, and epidemiologists use the detection of viremia to identify infected individuals within a population. Frequently, it may be difficult, or technically impossible, to quantify infectious particles in the blood, as is the case for hepatitis B virus. In these situations, the presence of characteristic viral proteins, such as the reverse transcriptase for human immunodeficiency virus type 1, and the presence of the viral genome provide surrogate markers for viremia.

However, the presence of infectious virus particles in the blood also presents practical problems. Infections can be spread inadvertently in the population when pooled blood from thousands of individuals is used for therapeutic purposes (transfusions) or as a source of therapeutic proteins (gamma globulin or blood-clotting factors). We have learned from unfortunate experience that bloodborne viruses, such as hepatitis viruses and human immunodeficiency virus type 1, can be spread by contaminated blood and blood products. The World Health Organization estimates that, as of 2000, inadequate blood screening resulted in 1 million new human immunodeficiency virus type 1 infections worldwide . Careful screening for these viruses in blood supplies before transfusion into patients is now standard procedure. However, sensitive detection methods and stringent purification protocols are useful only when we know what we are looking for; as-yet-undiscovered viruses may still be transmitted through the blood supply (Box 2.9).

BOX 2.9

      TERMINOLOGY

       The viruses in your blood

      If you have ever received a blood transfusion, along with the red blood cells, leukocytes, plasma, and other components, you also were likely infused with a collection of viruses. A recent study of the blood virome of more than 8,000 healthy individuals revealed a total of 19 different DNA viruses in 42% of the subjects.

      Viral DNA sequences were identified among the genome sequences of 8,240 individuals that were determined from blood. Of the 1 petabyte (1 million gigabytes) of sequence data that were generated, ∼5% did not correspond to human DNA. Within this fraction, sequences of 94 different viruses were identified. Nineteen of these were human viruses. The method is not expected to reveal RNA viruses except retroviruses that are integrated as DNA copies in the host chromosomes.

      The most common human viruses identified were herpesviruses, including cytomegalo virus, EpsteinBarr virus, herpes simplex virus, and human herpes viruses 7 and 8, found in 14 to 20% of individuals. Anelloviruses, small viruses with a circular genome, were found in 9% of the samples. Other viruses found in less than 1% of the samples included papillomaviruses, parvoviruses, polyomavirus, adenovirus, human immunodeficiency virus type 1, and human Tcell lymphotropic virus (the latter two integrated into host DNA).

      The other