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).
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 75 viruses are likely contaminants from laboratory reagents or the environment. These include sequences from nonhuman retroviruses, four different giant DNA viruses, and a virus of bees, all found in fewer than 10 samples. These findings illustrate the challenge in distinguishing bona fide human viruses from contaminants.
Identifying viruses in blood is an important objective for ensuring the safety of the blood supply. Donor blood is currently screened for human immunodeficiency virus types 1 and 2, human T-cell lymphotropic virus-1 and -2, hepatitis C virus, hepatitis B virus, West Nile virus, and Zika virus. These viruses are pathogenic for humans and can be transmitted via the blood. Some viruses, such as anelloviruses and pegiviruses, are in most donated blood, yet their pathogenic potential is unknown. It is not feasible to reject donor blood that contains any type of viral nucleic acid—if we did, we would not have a blood supply.
Continuing studies of the blood virome are needed to define which viruses should be tested for in donated blood. The human papillomavirus (17 people), Merkel cell polyomavirus (49 people), human herpesvirus type 8 (3 people), and adenovirus (9 people) detected in this study could be transmitted in the blood, and their presence should be monitored in future studies.
It is important to emphasize that this work describes only viral DNA sequences, and not infectious virus particles. The blood supply is screened by nucleic acid tests, but it is crucial to determine if infectious virus particles are also present . If viral DNA is present in blood but particles are never found, then it might not be necessary to reject blood based on the presence of certain sequences.
Moustafa A, Xie C, Kirkness E, Biggs W, Wong E, Turpaz Y, Bloom K, Delwart E, Nelson KE, Venter JC, Telenti A. 2017. The blood DNA virome in 8,000 humans. PLoS Pathog 13:e1006292.
Neural Spread
Some viruses spread from the primary site of infection by entering local nerve endings. In some cases, neuronal spread is the definitive characteristic of pathogenesis, notably by rabies virus and alphaherpesviruses, which cause infections that primarily impact neuronal function or survival. In other cases, invasion of the nervous system is a rare, typically dead-end, diversion from the normal site of reproduction (e.g., poliovirus, reovirus). Mumps virus, rubella virus, human immunodeficiency virus type 1, and measles virus can reproduce in the brain but access the central nervous system by the hematogenous route, often ferried into the brain by infected lymphocytes or monocytes. The molecular mechanisms that dictate spread into the brain by neural or hematogenous pathways are not well understood, and the way these viruses are defined can lead to further confusion (Box 2.10). For those neurotropic viruses that enter the brain via neuronal circuitry, viral reproduction usually occurs first in nonneuronal cells such as muscle cells near the site of infection. Following reproduction in these cells, virus particles subsequently spread into afferent (e.g., sensory) or efferent (e.g., motor) nerve fibers that innervate the infected tissue, usually crossing neuromuscular junctions to do so (Fig. 2.16).
Neurons are polarized cells with structurally and functionally distinct processes (axons and dendrites) that can be separated by enormous distances. For example, in adult humans, the axon terminals of motor neurons that control stomach muscles can be 50 centimeters away from the cell bodies and dendrites in the brain stem. Certainly, neurotropic viruses do not traverse these great distances by Brownian (random) motion. Rather, the neuronal cytoskeleton, including microtubules and actin, provides the “train tracks” that enable movement of mitochondria, synaptic vesicles, and virus particles to and from the synapse. Molecular motor proteins, such as dyneins and kinesins, are the “engines” that move along these cellular highways (Box 2.11). Drugs, such as colchicine, that disrupt microtubules efficiently block the spread of many neurotropic viruses from the site of peripheral inoculation to the central nervous system.
With few exceptions, cells of the peripheral nervous system are the first to be infected by neurotropic viruses. These neurons represent the first cells in circuits connecting the innervated peripheral tissue with the spinal cord and brain. Once in the nervous system, alphaherpesviruses and some rhabdoviruses (e.g., rabies virus), flaviviruses (e.g., West Nile virus), and paramyxoviruses (e.g., measles and canine distemper virus) can spread among neurons connected by synapses (Box 2.11). Virus spread by this mode can continue through chains of connected neurons of the peripheral nervous system and may eventually reach the spinal cord and brain, often with devastating
