The Nature of viruses Capsid(protein sheath) Envelope Viral structure DNa Envelope All viruses have the same basic struc ture: a core of nucleic acid surrounde y protein. Individual viruses contain ingle type of nucleic acid, eithe dnA or RNA. The dna or rna enome may be linear or circular, and single-stranded or double-stranded Viruses are frequently classified by the nature of their genomes. RNA-based (b)Tobacco mosaic virus (c) Human immunodeficiency (TMV virus(HIv) viruses are known as retroviruses Nearly all viruses form a protein FIGURE 33.3 sheath, or capsid, around their nucleic The structure of a bacterial, plant, and animal virus (a)Bacterial viruses, called acid core. The capsid is composed of bacteriophages, often have a complex structure. (b)TMV infects plants and consists of one to a few different protein molecules 2130 identical protein molecules (purple) that form a cylindrical coat around the single repeated many times(figure 33.3)In strand of RNA (greem ). The RNA backbone determines the shape of the virus and is some viruses, specialized enzymes are protected by the identical protein molecules packed tightly around it. (e) In the human viruses form an envelope around the Protein envelope capsid rich in proteins, lipids, and glyco protein molecules. While some of the material of the envelope is derived from the host cells new program is not itself a computer and cannot make membrane, the envelope does contain proteins derived copies of itself when it is outside the computer, lying on from viral genes in virtually every kind of organism that set of instructions the desk. The introduced program, like a virus, is simply a has been investigated for their presence. However, each of cell types. The 'plicate in only a very limited number utilize the cellular machinery of their hosts. Viruses code type of virus car suitable cells for a particular virus are heir genes on a single type of nucleic acid, either DNA or ferred to as its host range. The size of the RNA, but viruses lack ribosomes and the enzymes neces- host range reflects the coevolved histories of the virus and sary for protein synthesis. Viruses are able to reproduce be- its potential hosts. A recently discovered herpesvirus cause their genes are translated into proteins by the cell's turned lethal when it expanded its host range from the genetic machinery. These proteins lead to the production African elephant to the Indian elephant, a situation made of more viruses possible through cross-species contacts between elephants in zoos. Some viruses wreak havoc on the cells they infect; many others produce no disease or other outward sign of Viral Shape their infection. Still other viruses remain dormant for Most viruses have an overall structure that is either helical years until a specific signal triggers their expression. a or isometric. Helical viruses, such as the tobacco mosaic given organism often has more than one kind of virus. virus, have a rodlike or threadlike appearance. Isometric This suggests that there may be many more kinds of viruses have a roughly spherical shape whose geometry is viruses than there are kinds of organisms--perhaps mil evealed only under the highest magnification. lions of them. Only a few thousand viruses have been de The only structural pattern found so far among isomet scribed at this point ric viruses is the icosahedron, a structure with 20 equilat- eral triangular facets, like the adenovirus shown in figure Viral Replication 33.2. Most viruses are icosahedral in basic structure. The icosahedron is the basic design of the geodesic dome. It is An infecting virus can be thought of as a set of instruc- the most efficient symmetrical arrangement that linear tions, not unlike a computer program. A computers oper- subunits can take to form a shell with maximum internal ation is directed by the instructions in its operating pro- gram, just as a cell is directed by DNA-encoded instructions. A new program can be introduced into the computer that will cause the computer to cease what it is doing and devote all of its energies to another activity, Viruses occur in all organisms and can only reproduce of the introduced program. The within living cells. Most are icosahedral in structure such as making copies Chapter 33 Viruses 667
The Nature of Viruses Viral Structure All viruses have the same basic structure: a core of nucleic acid surrounded by protein. Individual viruses contain only a single type of nucleic acid, either DNA or RNA. The DNA or RNA genome may be linear or circular, and single-stranded or double-stranded. Viruses are frequently classified by the nature of their genomes. RNA-based viruses are known as retroviruses. Nearly all viruses form a protein sheath, or capsid, around their nucleic acid core. The capsid is composed of one to a few different protein molecules repeated many times (figure 33.3) In some viruses, specialized enzymes are stored within the capsid. Many animal viruses form an envelope around the capsid rich in proteins, lipids, and glycoprotein molecules. While some of the material of the envelope is derived from the host cell’s membrane, the envelope does contain proteins derived from viral genes as well. Viruses occur in virtually every kind of organism that has been investigated for their presence. However, each type of virus can replicate in only a very limited number of cell types. The suitable cells for a particular virus are collectively referred to as its host range. The size of the host range reflects the coevolved histories of the virus and its potential hosts. A recently discovered herpesvirus turned lethal when it expanded its host range from the African elephant to the Indian elephant, a situation made possible through cross-species contacts between elephants in zoos. Some viruses wreak havoc on the cells they infect; many others produce no disease or other outward sign of their infection. Still other viruses remain dormant for years until a specific signal triggers their expression. A given organism often has more than one kind of virus. This suggests that there may be many more kinds of viruses than there are kinds of organisms—perhaps millions of them. Only a few thousand viruses have been described at this point. Viral Replication An infecting virus can be thought of as a set of instructions, not unlike a computer program. A computer’s operation is directed by the instructions in its operating program, just as a cell is directed by DNA-encoded instructions. A new program can be introduced into the computer that will cause the computer to cease what it is doing and devote all of its energies to another activity, such as making copies of the introduced program. The new program is not itself a computer and cannot make copies of itself when it is outside the computer, lying on the desk. The introduced program, like a virus, is simply a set of instructions. Viruses can reproduce only when they enter cells and utilize the cellular machinery of their hosts. Viruses code their genes on a single type of nucleic acid, either DNA or RNA, but viruses lack ribosomes and the enzymes necessary for protein synthesis. Viruses are able to reproduce because their genes are translated into proteins by the cell’s genetic machinery. These proteins lead to the production of more viruses. Viral Shape Most viruses have an overall structure that is either helical or isometric. Helical viruses, such as the tobacco mosaic virus, have a rodlike or threadlike appearance. Isometric viruses have a roughly spherical shape whose geometry is revealed only under the highest magnification. The only structural pattern found so far among isometric viruses is the icosahedron, a structure with 20 equilateral triangular facets, like the adenovirus shown in figure 33.2. Most viruses are icosahedral in basic structure. The icosahedron is the basic design of the geodesic dome. It is the most efficient symmetrical arrangement that linear subunits can take to form a shell with maximum internal capacity. Viruses occur in all organisms and can only reproduce within living cells. Most are icosahedral in structure. Chapter 33 Viruses 667 Capsid (protein sheath) DNA Envelope protein Envelope Capsid Enzyme RNA (a) Bacteriophage (b) Tobacco mosaic virus (TMV) (c) Human immunodeficiency virus (HIV) RNA Proteins FIGURE 33.3 The structure of a bacterial, plant, and animal virus. (a) Bacterial viruses, called bacteriophages, often have a complex structure. (b) TMV infects plants and consists of 2130 identical protein molecules (purple) that form a cylindrical coat around the single strand of RNA (green). The RNA backbone determines the shape of the virus and is protected by the identical protein molecules packed tightly around it. (c) In the human immunodeficiency virus (HIV), the RNA core is held within a capsid that is encased by a protein envelope
33.2 Bacterial viruses exhibit two sorts of reproductive cycles Bacteriophages cycle(figure 33.5). The T-series bacteriophages are all vir ulent viruses, multiplying within infected cells and even- Bacteriophages are viruses that infect bacteria. They are tually lysing(rupturing)them. However, they vary consid- diverse both structurally and functionally, and are united erably as to when they become virulent within their host olely by their occurrence in bacterial hosts. Many of these cells bacteriophages, called phages for short, are large and com- plex, with relatively large amounts of DNA and proteins The lysogenic Cycle Some of them have been named as members of a "t" series 1, T2, and so forth); others have been given different Many bacteriophages do not immediately kill the cells they kinds of names. To illustrate the diversity of these viruses, infect, instead integrating their nucleic acid into the T3 and T7 phages are icosahedral and have short tails. In genome of the infected host cell. While residing there, it is contrast, the so-called T-even phages(T2, T4, and T6) called a prophage. Among the bacteriophages that do this have an icosahedral head, a capsid that consists primarily of is the lambda(x) phage of Escbericbia coli. We know as three proteins, a connecting neck with a collar and long much about this bacteriophage as we do about virtually any whiskers, "a long tail, and a complex base plate(figure other biological particle; the complete sequence of its 334) 48, 502 bases has been determined. At least 23 proteins are associated with the development and maturation of lambda The lytic cycle phage, and many other enzymes are involved in the inte- the host During the process of bacterial infection by T4 phage, at The integration of a virus into a cellular genome is least one of the tail fibers of the phage--they are normally called lysogeny. At a later time, the prophage may exit the held near the phage head by the whiskers"contacts the genome and initiate virus replication. This sort of repro lipoproteins of the host bacterial cell wall. The other tail ductive cycle, involving a period of genome integration, is fibers set the phage perpendicular to the surface of the bac- called a lysogenic cycle. Viruses that become stably inte- cerium and bring the base plate into contact with the cell grated within the genome of their host cells are called lyso- surface. The tail contracts, and the tail tube passes through genic viruses or temperate viruses an opening that appears in the base plate, piercing the bac terial cell wall. The contents of the head, mostly DNA, are Bacteriophages are a diverse group of viruses that then injected into the host cytoplasm attack bacteria. Some kill their host in a lytic cy When a virus kills the infected host cell in which others integrate into the host's genome, initiating a replicating, the reproductive cycle is referred to as a lytic Head (protein sheath Whiskers FIGURE 33. 4 A bacterial virus complex structure.(a) Electron micrograph (b)diagram of the structure of a T4 05 um Tail fiber 668 Part IX Viruses and Simple organism
Bacteriophages Bacteriophages are viruses that infect bacteria. They are diverse both structurally and functionally, and are united solely by their occurrence in bacterial hosts. Many of these bacteriophages, called phages for short, are large and complex, with relatively large amounts of DNA and proteins. Some of them have been named as members of a “T” series (T1, T2, and so forth); others have been given different kinds of names. To illustrate the diversity of these viruses, T3 and T7 phages are icosahedral and have short tails. In contrast, the so-called T-even phages (T2, T4, and T6) have an icosahedral head, a capsid that consists primarily of three proteins, a connecting neck with a collar and long “whiskers,” a long tail, and a complex base plate (figure 33.4). The Lytic Cycle During the process of bacterial infection by T4 phage, at least one of the tail fibers of the phage—they are normally held near the phage head by the “whiskers”—contacts the lipoproteins of the host bacterial cell wall. The other tail fibers set the phage perpendicular to the surface of the bacterium and bring the base plate into contact with the cell surface. The tail contracts, and the tail tube passes through an opening that appears in the base plate, piercing the bacterial cell wall. The contents of the head, mostly DNA, are then injected into the host cytoplasm. When a virus kills the infected host cell in which it is replicating, the reproductive cycle is referred to as a lytic cycle (figure 33.5). The T-series bacteriophages are all virulent viruses, multiplying within infected cells and eventually lysing (rupturing) them. However, they vary considerably as to when they become virulent within their host cells. The Lysogenic Cycle Many bacteriophages do not immediately kill the cells they infect, instead integrating their nucleic acid into the genome of the infected host cell. While residing there, it is called a prophage. Among the bacteriophages that do this is the lambda () phage of Escherichia coli. We know as much about this bacteriophage as we do about virtually any other biological particle; the complete sequence of its 48,502 bases has been determined. At least 23 proteins are associated with the development and maturation of lambda phage, and many other enzymes are involved in the integration of these viruses into the host genome. The integration of a virus into a cellular genome is called lysogeny. At a later time, the prophage may exit the genome and initiate virus replication. This sort of reproductive cycle, involving a period of genome integration, is called a lysogenic cycle. Viruses that become stably integrated within the genome of their host cells are called lysogenic viruses or temperate viruses. Bacteriophages are a diverse group of viruses that attack bacteria. Some kill their host in a lytic cycle; others integrate into the host’s genome, initiating a lysogenic cycle. 668 Part IX Viruses and Simple Organisms 33.2 Bacterial viruses exhibit two sorts of reproductive cycles. .05 µm (b) Head Capsid (protein sheath) DNA Whiskers Tail Tail fiber Base plate Neck FIGURE 33.4 A bacterial virus. Bacteriophages exhibit a complex structure. (a) Electron micrograph and (b) diagram of the structure of a T4 (a) bacteriophage.
Lysis of 32。 As sembly Bacterial y FIGURE 33.5 c and lys bacteriophage. In the lytic cycle, vegetative the bacteriophage exists as viral DNA free in the bacterial host cell's cytoplasm; the viral DNA Viral dna directs the production of new injected into cell viral particles by the host cell nduction of until the virus kills the cell by Reduction to lysis In the lysogenic cycle, the bacteriophage DNA is integrated into the large, circular DNA molecule of the host bacterium Lysogenic and is reproduced along with the host dna as the bacterium Viral DNA integrated replicates. It may co replicate and produce lysogenic cteria or enter the lytic cycle and kill the cell. Bacteriophages are much smaller relative to their hosts than illustrated in this Reproduction of lysogenic bacteria Cell Transformation and Phage cteria Vibrio cholerae usually exists in a harmless form, but Conversion a second disease-causing, virulent form also occurs. In this latter form, the bacterium causes the deadly disease holera, but how the bacteria changed from harmless to cycle, virus genes are often expressed. The RNA poly- deadly was not known until recently. Research now show merase of the host cell reads the viral genes just as if they that a bacteriophage that infects V. cholerae introduces into were host genes. Sometimes, expression of these genes has the host bacterial cell a gene that codes for the cholera an important eftect on the host cell, altering it in novel toxin. This gene becomes incorporated into the bacterial chromosome where it is translated along with the other troduction of foreign DNA is called transformation. host genes, thereby converting the benign bacterium to a When the foreign dNa is contributed by a bacterial virus the alteration is called phage conversion I pili(see chapter 34); in further experiments, mutant ba teria that did not have pili were resistant to infection by the bacteriophage. This discovery has important implications Phage Conversion of the Cholera-Causin in efforts to develop vaccines against cholera, which have Bacterium been unsuccessful up to this point. An important example of this sort of phage conversion di rected by viral genes is provided by the bacterium responsi- Bacteriophages convert Vibrio cholerae bacteria from ble for an often-fatal human disease. The disease-causing harmless gut residents into disease-causing agents Chapter 33 Virus 669
Cell Transformation and Phage Conversion During the integrated portion of a lysogenic reproductive cycle, virus genes are often expressed. The RNA polymerase of the host cell reads the viral genes just as if they were host genes. Sometimes, expression of these genes has an important effect on the host cell, altering it in novel ways. The genetic alteration of a cell’s genome by the introduction of foreign DNA is called transformation. When the foreign DNA is contributed by a bacterial virus, the alteration is called phage conversion. Phage Conversion of the Cholera-Causing Bacterium An important example of this sort of phage conversion directed by viral genes is provided by the bacterium responsible for an often-fatal human disease. The disease-causing bacteria Vibrio cholerae usually exists in a harmless form, but a second disease-causing, virulent form also occurs. In this latter form, the bacterium causes the deadly disease cholera, but how the bacteria changed from harmless to deadly was not known until recently. Research now shows that a bacteriophage that infects V. cholerae introduces into the host bacterial cell a gene that codes for the cholera toxin. This gene becomes incorporated into the bacterial chromosome, where it is translated along with the other host genes, thereby converting the benign bacterium to a disease-causing agent. The transfer occurs through bacterial pili (see chapter 34); in further experiments, mutant bacteria that did not have pili were resistant to infection by the bacteriophage. This discovery has important implications in efforts to develop vaccines against cholera, which have been unsuccessful up to this point. Bacteriophages convert Vibrio cholerae bacteria from harmless gut residents into disease-causing agents. Chapter 33 Viruses 669 Lysis of cell Uninfected cell Virus attaching to cell wall Bacterial chromosome Viral DNA injected into cell Viral DNA integrated into bacterial chromosome Reproduction of lysogenic bacteria Lysogenic cycle Lytic cycle Reduction to prophage Induction of prophage to vegetative virus Replication of vegetative virus Assembly of new viruses using bacterial cell machinery FIGURE 33.5 Lytic and lysogenic cycles of a bacteriophage. In the lytic cycle, the bacteriophage exists as viral DNA free in the bacterial host cell’s cytoplasm; the viral DNA directs the production of new viral particles by the host cell until the virus kills the cell by lysis. In the lysogenic cycle, the bacteriophage DNA is integrated into the large, circular DNA molecule of the host bacterium and is reproduced along with the host DNA as the bacterium replicates. It may continue to replicate and produce lysogenic bacteria or enter the lytic cycle and kill the cell. Bacteriophages are much smaller relative to their hosts than illustrated in this diagram
33.3 HIV is a complex animal virus AIDS a diverse array of viruses occur among animals. a good way to gain a general idea of what they are like is to look at one animal virus in detail here we will look at the virus responsible for a comparatively new and fatal viral disease, acquired immunodeficiency syndrome(AIDS). AIDS was first reported in the United States in 1981. It was not long before the infectious agent, a retrovirus called human im munodeficiency virus(HIV), was identified by laboratories in France and the United States. Study of Hiv revealed it to be closely related to a chimpanzee virus, suggesting a recent host expansion to humans in central Africa from Infected humans have little resistance to infection. and nearly all of them eventually die of diseases that nonin-FIGURE336 fected individuals easily ward off. Few who contract The AIDS virus. HIV particles exit an infected CD4+T cell AIDS survive more than a few years untreated. The risk (both shown in false color). The free virus particles are able to f hiv transmission from an infected individual to a infect neighboring CD4+ T cells healthy one in the course of day-to-day contact is essen tially nonexistent. However, the transfer of body fluids, such as blood, semen, or vaginal fluid, or the use of non- fectious, which makes the spread of Hiv very difficult to con sterile needles, between infected and healthy individuals trol. The reason why Hiv remains hidden for so long seems poses a severe risk. In addition, HIV-infected mothers to be that its infection cycle continues throughout the 8-to can pass the virus on to their unborn children during 10-year latent period without doing serious harm to the in fetal development fected person. Eventually, however, a random mutational The incidence of aid owing very rapidly in the event in the virus allows it to quickly overcome the immune United States. It is estimated that over 33 million people defense, starting AIDS orldwide are infected with HIV. Many-perhaps all of them-will eventually come down with AIDS. Over 16 The HIv Infection Cycle million people have died already since the outbreak of the epidemic. AIDS incidence is already very high in many The HIV virus infects and eliminates key cells of the im- African countries and is growing at 20% worldwide. The mune system, destroying the body's ability to defend itself AIDS epidemic is discussed further in chapter 57. from cancer and infection. The way HIV infects humans (figure 33.7)pi ple of how animal How HIV Compromises the Immune System viruses replicate. Most other viral infections follow a simi- lar course, although the details of entry and replication dif- n normal individuals, an army of specialized cells patrols fer in individual cases the bloodstream, attacking and destroying any invading bacteria or viruses. In AIDS patients, this army of de- Attachment. When Hiv is introduced into the human fenders is vanquished. One special kind of white blood bloodstream, the virus particle circulates throughout the cell, called a CD4+ T cell(discussed further in chapter entire body but will only infect CD4+ cells. Most other ani- 57)is required to ror se the defending cells to action. In mal viruses are similarly narrow in their requirements; he AIDS patients, the virus homes in on CD4+ T cells, in- patitis goes only to the liver, and rabies to the bra fecting and killing them until none are left(figure 33. 6) How does a virus such as HIV recognize a specific kind Without these crucial immune system cells, the body of target cell? Recall from chapter 7 that every kind of cell cannot mount a defense against invading bacteria or in the human body has a specific array of cell-surface glyco viruses. AIDS patients die of infections that a healthy protein markers that serve to identify them to other, similar person could fight off. cells. Each HIV particle possesses a glycoprotein(called toms tv pically do not begin to develop until gp120)on its surface that precisely fits a cell-surface fter a long latency period, generally 8 to 10 years after the marker itial infection with HIV. during this long interval, carriers m cel, protein called CD4 on the surfaces of immune sys- called macrophages and T cells. Macrophages are of Hiv have no clinical symptoms but are apparently fully in- infected first. 670 Part IX Viruses and Simple organism
AIDS A diverse array of viruses occur among animals. A good way to gain a general idea of what they are like is to look at one animal virus in detail. Here we will look at the virus responsible for a comparatively new and fatal viral disease, acquired immunodeficiency syndrome (AIDS). AIDS was first reported in the United States in 1981. It was not long before the infectious agent, a retrovirus called human immunodeficiency virus (HIV), was identified by laboratories in France and the United States. Study of HIV revealed it to be closely related to a chimpanzee virus, suggesting a recent host expansion to humans in central Africa from chimpanzees. Infected humans have little resistance to infection, and nearly all of them eventually die of diseases that noninfected individuals easily ward off. Few who contract AIDS survive more than a few years untreated. The risk of HIV transmission from an infected individual to a healthy one in the course of day-to-day contact is essentially nonexistent. However, the transfer of body fluids, such as blood, semen, or vaginal fluid, or the use of nonsterile needles, between infected and healthy individuals poses a severe risk. In addition, HIV-infected mothers can pass the virus on to their unborn children during fetal development. The incidence of AIDS is growing very rapidly in the United States. It is estimated that over 33 million people worldwide are infected with HIV. Many—perhaps all of them—will eventually come down with AIDS. Over 16 million people have died already since the outbreak of the epidemic. AIDS incidence is already very high in many African countries and is growing at 20% worldwide. The AIDS epidemic is discussed further in chapter 57. How HIV Compromises the Immune System In normal individuals, an army of specialized cells patrols the bloodstream, attacking and destroying any invading bacteria or viruses. In AIDS patients, this army of defenders is vanquished. One special kind of white blood cell, called a CD4+ T cell (discussed further in chapter 57) is required to rouse the defending cells to action. In AIDS patients, the virus homes in on CD4+ T cells, infecting and killing them until none are left (figure 33.6). Without these crucial immune system cells, the body cannot mount a defense against invading bacteria or viruses. AIDS patients die of infections that a healthy person could fight off. Clinical symptoms typically do not begin to develop until after a long latency period, generally 8 to 10 years after the initial infection with HIV. During this long interval, carriers of HIV have no clinical symptoms but are apparently fully infectious, which makes the spread of HIV very difficult to control. The reason why HIV remains hidden for so long seems to be that its infection cycle continues throughout the 8- to 10-year latent period without doing serious harm to the infected person. Eventually, however, a random mutational event in the virus allows it to quickly overcome the immune defense, starting AIDS. The HIV Infection Cycle The HIV virus infects and eliminates key cells of the immune system, destroying the body’s ability to defend itself from cancer and infection. The way HIV infects humans (figure 33.7) provides a good example of how animal viruses replicate. Most other viral infections follow a similar course, although the details of entry and replication differ in individual cases. Attachment. When HIV is introduced into the human bloodstream, the virus particle circulates throughout the entire body but will only infect CD4+ cells. Most other animal viruses are similarly narrow in their requirements; hepatitis goes only to the liver, and rabies to the brain. How does a virus such as HIV recognize a specific kind of target cell? Recall from chapter 7 that every kind of cell in the human body has a specific array of cell-surface glycoprotein markers that serve to identify them to other, similar cells. Each HIV particle possesses a glycoprotein (called gp120) on its surface that precisely fits a cell-surface marker protein called CD4 on the surfaces of immune system cells called macrophages and T cells. Macrophages are infected first. 670 Part IX Viruses and Simple Organisms 33.3 HIV is a complex animal virus. FIGURE 33.6 The AIDS virus. HIV particles exit an infected CD4+ T cell (both shown in false color). The free virus particles are able to infect neighboring CD4+ T cells
HIV CCR5 or CXCR4 Reverse transcriptase Viral RNA RNA Double- stranded CD4 receptor gp120 glycoprotein on the surface of HIv attaches to CD4 and Reverse transcriptase catalyzes the synthesis of a DNA copy of two coreceptors on the surface of a CD4+ cell. The viral the viral RNA. The host cell then synthesizes a com its enter the cell by endocytosis strand of dna exit by Viral DNA RNA Viral exit by The double-stranded DNA directs the synthesis of both HIV RNA and HIv proteins. out of the cell by exocytosis In T cells, however, HIV ruptures the cell, releasing free HIV back into the bloodstream FIGURE 33.7 The HIV infection cycle. The cycle begins and ends with free Hiv particles present in the bloodstream of its human host. These free viruses infect white blood cells called CD4+ t cells Entry into Macrophages. After docking onto the CD4 Entry into T Cells. During this time, HIV is con receptor of a macrophage, HIV requires a second stantly replicating and mutating. Eventually, by chance, macrophage receptor, called CCR5, to pull itself across the HIV alters the gene for gp120 in a way that causes the cell membrane. After gp120 binds to CD4 120 protein to change its second-receptor allegiance conformational change that allows it to bind to CCr5. The This new form of gp120 protein prefers to bind instead current model suggests that after the conformational change, to a different second receptor, CXCR4, a receptor that the second receptor passes the gp120-CD4 complex through occurs on the surface of T lymphocyte CD4+ cells. Soon the cell membrane, triggering passage of the contents of the the bodys T lymphocytes become infected with HIV HIV virus into the cell by endocytosis, with the cell mem- This has deadly consequences, as new viruses exit the cell brane folding inward to form a deep cavity around the virus. by rupturing the cell membrane, effectively killing the in fectedT cell. Thus the shift to the CXCr4 second re- Replication. Once inside the macrophage, the HiV parti- ceptor is followed swiftly by a steep drop in the number cle sheds its protective coat. This leaves virus RNA floating of T cells. This destruction of the body's T cells blocks in the cytoplasm, along with a virus enzyme that was also the immune response and leads directly to the onset of within the virus shell. This enzyme, called reverse tran scriptase, synthesizes a double strand of DNA complemen AIDS, with cancers and opportunistic infections free to tary to the virus RNA, often making mistakes and so intro- invade the defenseless hoas. ducing new mutations. This double-stranded dna directs the host cell machinery to produce many copies of the virus. HIV, the virus that causes AIDs is an RNA virus that Hiv does not rupture and kill the macrophage cells it in replicates inside human cells by first making a dNA fects. Instead, the new viruses are released from the cell by copy of itself. It is only able to gain entrance to thos exocytosis. HIV synthesizes large numbers of viruses in this ng a particular cell surface marker way, challenging the immune system over a period of years recognized by a glycoprotein on its own surface Chapter 33 Viruses 671
Entry into Macrophages. After docking onto the CD4 receptor of a macrophage, HIV requires a second macrophage receptor, called CCR5, to pull itself across the cell membrane. After gp120 binds to CD4, it goes through a conformational change that allows it to bind to CCR5. The current model suggests that after the conformational change, the second receptor passes the gp120-CD4 complex through the cell membrane, triggering passage of the contents of the HIV virus into the cell by endocytosis, with the cell membrane folding inward to form a deep cavity around the virus. Replication. Once inside the macrophage, the HIV particle sheds its protective coat. This leaves virus RNA floating in the cytoplasm, along with a virus enzyme that was also within the virus shell. This enzyme, called reverse transcriptase, synthesizes a double strand of DNA complementary to the virus RNA, often making mistakes and so introducing new mutations. This double-stranded DNA directs the host cell machinery to produce many copies of the virus. HIV does not rupture and kill the macrophage cells it infects. Instead, the new viruses are released from the cell by exocytosis. HIV synthesizes large numbers of viruses in this way, challenging the immune system over a period of years. Entry into T Cells. During this time, HIV is constantly replicating and mutating. Eventually, by chance, HIV alters the gene for gp120 in a way that causes the gp120 protein to change its second-receptor allegiance. This new form of gp120 protein prefers to bind instead to a different second receptor, CXCR4, a receptor that occurs on the surface of T lymphocyte CD4+ cells. Soon the body’s T lymphocytes become infected with HIV. This has deadly consequences, as new viruses exit the cell by rupturing the cell membrane, effectively killing the infected T cell. Thus, the shift to the CXCR4 second receptor is followed swiftly by a steep drop in the number of T cells. This destruction of the body’s T cells blocks the immune response and leads directly to the onset of AIDS, with cancers and opportunistic infections free to invade the defenseless body. HIV, the virus that causes AIDS, is an RNA virus that replicates inside human cells by first making a DNA copy of itself. It is only able to gain entrance to those cells possessing a particular cell surface marker recognized by a glycoprotein on its own surface. Chapter 33 Viruses 671 1 2 3 4 Reverse transcriptase catalyzes the synthesis of a DNA copy of the viral RNA. The host cell then synthesizes a complementary strand of DNA. The gp120 glycoprotein on the surface of HIV attaches to CD4 and one of two coreceptors on the surface of a CD4+ cell. The viral contents enter the cell by endocytosis. The double-stranded DNA directs the synthesis of both HIV RNA and HIV proteins. Complete HIV particles are assembled. In macrophages, HIV buds out of the cell by exocytosis. In T cells, however, HIV ruptures the cell, releasing free HIV back into the bloodstream. DNA Viral RNA Reverse transcriptase Doublestranded DNA Viral RNA CD4 receptor gp120 HIV CD4+ cell CCR5 or CXCR4 coreceptor DNA Viral RNA Viral proteins Viral exit by exocytosis in macrophages Viral exit by cell lysis in T cells FIGURE 33.7 The HIV infection cycle. The cycle begins and ends with free HIV particles present in the bloodstream of its human host. These free viruses infect white blood cells called CD4 T cells.