Fall 2006-



Fall 2006-

Partial study guidance for Exam 4 (Microbiology)

I told you to pay special attention to Chapters 54, 65, and 66 in the Murray et al. text. Focus on the following parts of these chapters.

Chapter 54: Human Herpesviruses

• Boxes 54-1, -2, -3, -4, (not box 54-5) -6, -7, -8 –9 –10, 11, -12, -13

• Tables 54-1, -2, -3 (only heterophile antibody entry for Table 54-3)

• Section on “Treatment, prevention, and control” on pages 549-550

• HSV replication scheme described on page 544 and diagramed in figure 6-12 on page 58

• “Case studies and questions” on page 563

Box 54-1

*Herpes viruses have large, enveloped icosadeltahedral capsids containing double-stranded DNA genomes. (fragile so susceptible to heat and drying)

*Herpes viruses encode many proteins that manipulate the host cell and immune response

*Herpes viruses encode enzymes (DNA polymerase) that promote viral DNA replication and that are good targets for antiviral drugs.

*DNA replication and capsid assemble occurs in the nucleus

*Virus is released by exocytosis, cell lysis, and through cell-cell bridges

*Herpes viruses can cause lytic, persitent, latent, and , for Epstein-Barr virus, immortalizing infections

*Herpes viruses are ubiquitous

*Cell-mediated immunity is required for control

*Generally require direct inoculation (mucous membranes more susceptible than skin)

Table 54-1

|Subfamily |Virus |Primary Target Cell |Site of Latency |Means of |

| | | | |Spread |

|Human Herpes Virus I |Herpes Simplex Type I |Mucoepithelial Cells |Neuron |Close Contact |

|(alpha) | | | | |

|Human Herpes Virus II |Herpes Simplex Type II |Mucoepithelial Cells |Neuron |Close Contact (sexually |

|(alpha) | | | |transmitted |

|Human Herpes Virus III |Varicella-Zoster virus |Mucoepithelial Cells |Neuron |Respiratory and close contact|

|(alpha) | | | | |

|Human Herpes Virus IV |Epstein-Barr Virus |B cells and Epithelial Cells |B cell |Saliva (kissing disease) |

|(gamma) | | | | |

|Human Herpes Virus 8 |Kaposi’s sarcoma-related virus |Lymphocyte and other cells | B cell |Close Contact (sexual) |

|(gamma) | | | | |

|Human herpes virus 5 (beta)|Cytomegalovirus |Monocyte, lymphocyte, and epithelial |Monocyte, lymphocyte |Close contact, transfusions, |

| | |cells | |tissue transplant, and |

| | | | |congenital |

|Human Herpes Virus 6 |Herpes lymphotropic virus |T cells |T cells |Respiratory and close contact|

|Human Herpes virus 7 |Human Herpes Virus 7 |T cells | T cells | ? |

Pg 544 Replication of HSV

1. HSV-2 binds quickly and efficiently to cells through initial interaction with heparin sulfate, a proteoglycan found on the outside of many cell types, and then a tighter interaction with receptor proteins at the cell surface.

2. Penetration into the cell requires interaction with nectin-1 alpha, an intercellular adhesion molecule that is a member of the immunoglobulain protein family and similar to the poliovirus receptor. Nectin -1 alpha is found on most cells and neurons. Another receptor is HveA, a member of the tumor necrosis factor receptor family which is expressed on activated T cells, neurons, and other cells.

3. HSV penetrates the host cell by fusion of its envelope with the cell surface membrane.

4. On fusion, the virion releases its capsid into the cytoplasm, along with a protein that promotes the initiation of viral gene transcription, a viral encoded protein kinase, and cytotoxic proteins. VHS proteins target and degrade mRNAs to shut down translation in the host cell to doom the cell to death.

5. The capsid docks with a nuclear pore and delivers the genome into the nucleus.

6. Immediate early gene products include DNA binding proteins, which stimulate DNA synthesis and promote the transcription of the early viral genes and also host shut down factors.

Early proteins include the DNA-dependent DNA polymerase and thymidine kinase.

7. The genome is replicated as soon as the polymerase is synthesized. Circular, end to end concatameric forms of the genome are made initially. Later in the infection, the DNA is replicated by a rolling circle mechanism to produce a linear string of genomes. The concatamers are cleaved into individual genomes as the DNA is sucked into a procapsid.

8. Genome replication triggers transcription of the late genes. Late proteins consist mainly of strucutral proteins which are generated after viral genome replication has begun.

9. Capsid proteins are then transported to the nucleus where they are assembled into empty procapsids and filled with DNA. DNA containing capsids associate with viral protein disrupted nuclear membranes and bud into and then out of the ER into the cytoplasm.

10. Viral glycoproteins are synthesized and processed like cellular glycoproteins. Tegument proteins associate with the viral capsid in the cytoplasm and then the capsid buds into a portion of the trans-Golgi network to acquire their glycoprotein containing envelope.

11. The virus is released by excocytosis or cell lysis. Virus induced synctyia by spread between cells through intracellular bridges also spreads the infection.

12. Transcripton of the latency genes and no other viral gene will result in latency. HSV infection of neurons may result in virus replication or establishment to latency.

Box 54-2 Disease Mechanisms for HSV I and HSV II

*Disease is initiated by direct contact and depends on infected tissue (oral, genital, brain)

*Virus causes direct cytopathologic effects

*Virus avoids antibody by cell-cell spread (syncytia)

*Virus is reactivated from latency by stress or immune suppression

*Cell-mediated immunity is required for resolution with limited role for antibody

*Cell mediated (TH1 and cytotoxic killer T cells) immunopathologic effects to contribute to symptoms

*HSV can cause lytic infections of most cells, persistent infections of lymphocytes and macrophages, and latent infection of neurons

Box 54-3 Triggers of HSV Recurrences

• UV-B radiation (skiing, tanning)

• Fever

• Emotional stress

• Physical stress (irritation)

• Menstruation

• Spicy foods, acidic foods, allergic foods

• Immmunosuppression

o Transient (stress related)

o Chemotherapy, radiotherapy

o HIV

Box 54-4 Epidemiology of Herpes Simplex Virus (HSV)

Disease/Viral Factors

*Virus causes lifelong infection

*Recurrent disease is source of contagion

*Virus may cause asymptomatic shedding

Transmission

*Virus is transmitted in saliva, in vaginal secretions, and by contact with lesion fluid (mixing and matching of mucous membranes)

*Virus is transmitted orally and sexually and by placement into eyes and breaks in skin

*HSV-1 is generally transmitted orally; HSV-2 is generally transmitted sexually

Who is at Risk?

*Children and sexually active people; at risk for classic presentations of HSV-1 and HSV-2, respectively

*Physicians, nurse, dentists, and others in contact with oral and genital secretions (herpetic whitlow)

*Immunocompromised people and neonates; At risk for disseminated, life-threatening disease

Geography/Season

*Virus is found worldwide

*There is no seasonal incidence

Mode of Control

• Anitviral drugs are available

• no vaccine is available

• Health care workers should wear gloves to prevent herpetic whitlow

• People with active genital lesions should refrain from intercourse until lesions are completely reepithelialized

Table 54-2 Laboratory DX of HSV Infections

|Approach |Test/Comment |

|Direct microscopic examination of cells from base of lesion |Tzanck smear shows multinucleated giant cells and Cowdry type A |

| |inclusion bodies |

|Cell Culture |HSV replicates and causes identifiable cytopathologic effects in most |

| |cell cultures |

|Assay of tissue biopsy, smear, CSF, or vesicular fluid for HSV antigen|Enzyme immunoassay, immunofluorescent stain, insitu DNA probe |

|or genome |analysis, and polymerase chain reaction (PCR) |

|HSV type distinction (HSV- 1 vs HSV -2) |Type-specific antibody, DNA maps of restriction enzyme fragments, |

| |sodium dodecyl sulfate-gel protein patterns, DNA probe analysis, and |

| |PCR |

|Serology |Serology is not useful except for epidemiology |

Treatment, Prevention, and Control pg 549-550

*HSV encodes several target enzymes for antiviral drugs. Most antiherpes drugs are nucleoside analogues and other inhibitors of the viral DNA polymerase, the best antiviral target.

*None of the drug treatments can eliminate latent infection but only shortens the course of the primary or recurrent disease

*The prototypes FDA approved anti HSV drug is acyclovir.

*Valacyclovir, penciclovir, and famciclovir are related to acyclovir but have different properties

*Although Cidofovir and adefovir are active against HSV, cidofovir is only approved for treatment of CMV

*Phosphorylation of ACV and penciclovir by the viral thymidine kinase and cellular enzymes activates the drug as a substrate for the viral DNA polymerase. These drugs are then incorporated into the and prevent the elongation of the viral DNA

*ACV, valaciclovir, penciclovir and famciclovir are relatively nontoxic, are effective in treating serious presentations of HSV disease and first episodes of genital herpes, and are also used for prophylactic treatment

*The most prevalent form of resistance to these drugs results from mutations that inactivate the thymidine kinase, thereby preventing conversion of the dug to its active form. Mutation of the viral DNA polymerase also produces resistance but resistant strains are less virulent

*HSV-1 is transmitted most often from an active mucocutaneous lesion, so avoidance of direct contact with lesions reduces the risk of infection. Washing with soap readily disinfects the virus.

*killed subunit, vaccinia hybrid and DNA vaccines are being developed as well a glycoprotein D and defective infectious single cycle vaccines are being developed.

Box 54-6 Disease Mechanisms of Varicella-Zoster Virus (VZV)

*Initial replication is in the respiratory tract and generally acquired by inhalation

*VZV infects epithelial cells, fibroblasts, T cells, and neurons

*VZV can form syncytia and spread directly from cell to cell

*Virus is spread by viremia to skin and causes lesions in successive crops

*VZV can escape antibody clearance, and cell-mediated immune response is essential to control infection. Disseminated, life-threatening diseease can occur in immunocompromised people

*Virus establishes latent infection of neurons, usually dorsal root and cranial nerve ganglia

*Herpes zoster is a recurrent disease; it results from virus replication along the entire dermatome

*Herpes zoster may result from depression of cell-mediated immunity and other mechanisms of viral activation

Box 54-7 Epidemiology of Varicella-Zoster Virus

Disease/Viral Factors

• Virus causes lifelong infection

• *Recurrent disease is a source of contagion

Transmission

• Virus is transmitted mainly by respiratory droplets but also by direct contact

Who is at Risk?

*Children (ages 5-9); Mild classic disease

*Teens and adults: at risk for more severe disease with potential pneumonia

*immunocompromised people and newborns: at risk for life-threatening pneumonia, encephalitis, and progressive disseminated varicella

*elderly and immunocompromised people: At risk for recurrent disease (herpes zoster (shingles))

Geography/Season

*Virus is found worldwide

*There is no seasonal incidence

Modes of Control

*Antiviral drugs are available

*Immunity may wane in the elderly population

*Varicella Zoster immunoglobulin is available fro immunocompromised people and staff exposed to virus, as well as newborns of mothers showing symptoms within 5 days of birth

*Live vaccine (Oka Strain) for children

Box 54-8 Disease Mechanisms of Epstein-Barr Virus

• Virus in saliva initiates infection of oral epithelia and spreads to B cells in lymphatic tissue

• There is no productive infection of epithelial and B cells

• Virus promotes growth of B cells (immortalizes)

• T cells kill and limit B-cell outgrowth. T cells are required for controlling infection. Antibody role is limited

• EBV establishes latency in memory B cells and is reactivated when the B cell is activated

• T-cell response (lymphocytosis)contributes to symptoms of infectious monomucleosis

• There is causative association with lympomha in immunosuppressed people and African children living in malarial regions (African Burkitt’s lymphoma) and with nasopharyngeal carcinoma in China

Table 54-3 Markers of EBV Infection

|Name |Characteristics |Biologic Association |Clinical Association |

|Heterophile antibody |Recognition of Paul-Bunnell antigen |EBV-induced B cell proliferation |Early symptoms occurs in more than|

| |on sheep, horse, or bovine |promotes production of heterophile |50% of patients |

| |erythrocytes |antibody | |

Box 54-9 Epidemiology of EBV

Disease/Viral Factors

*Virus causes lifelong infection

*Recurrent disease is cause of contagion

*Virus may cause asymptomatic shedding

Transmission

*transmission occurs via saliva, close oral contact (kissing disease) or sharing of items such as toothbrushes and cups

Who is at Risk?

*Children: Asymptomatic disease or mild symptoms

*Teenagers and adults: At risk for infectious mono

*immnunocompromised people: at highest risk for life threatening neoplastic disease such as lymphomas and also immunocompromised and AIDS patients are at high risk for hairy oral leukoplakia

Geography/Season

• Infectious mononucleosis has world wide distribution

• There is causative association with African Burkitt’s lymphoma in malaria belt of Africa

• There is no seasonal incidence

Modes of Control

• There are no modes of control

Box 54-10 Diagnosis of EBV

1. Symptoms

a. Mild headache, fatigue, fever

b. Triad: lymphadenopathy, splenomegaly, exudative pharyngitis

c. Other: Hepatitis, amipicillin induced rash

2. Complete Blood Cell count

a. Hyperplasia

b. Atypical lymphocytes (Downey Cells- T Cells) –disappear with resolution of disease

3. Heterophile antibody (transient

4. EBV- antigen specific antibody

Box 54-11 Disease Mechanisms of Cytomegalovirus (CMV)

• CMV is acquired from blood, tissue, and most body secretions

• CMV causes productive infection of epithelial and other cells

• CMV establishes latency in T cells, macrophages, and other cells ( an excellent parasite)

• Cell-mediated immunity is required for resolution and contributes to symptoms; role of antibody is limited

• Suppression of cell-mediated immunity allows recurrence and severe presentation

• CMV generally causes subclinical infection

• It is the most common viral cause of congenital defects

• It has the largest genome of the herpes virus family

Box 54-12 Epidemiology of CMV Infection

Disease/Viral Factors

• Virus causes lifelong infection

• Recurrent disease is source of contagion

• Virus may cause asymptomatic shedding

Transmission

• Transmission occurs via blood, organ transplants, and all secretions (urine, saliva, semen, cervical secretions, breast milk, tears)

• Virus is transmitted orally and sexually, in blood transfusions, in tissue transplants, in utero, at birth, and at nursing

Geography/Season

• Virus is found worldwide

• There is no seasonal incidence

Who is at Risk?

• Babies

• Babies of mothers who experience seroconversion during term: at high risk for congenital defects

• Sexually active people

• Blood and organ recipients

• Burn victims

• Immunocompromised people: symptomatic and recurrent disease

Modes of Control

• Antiviral drugs are available for patients with acquired immune deficiency syndrome (AIDS)

• Screening potential blood and organ donors for CMV reduces transmission of virus

Box 54-13 Clinical Summaries

• Primary oral herpes: A 5 year old boy has an ulcerative rash with vesicles around the mouth. Vesicles and ulcers also present within the mouth. Results of Tzanck smear show multinucleated giant cells (synctyia) and Cowdry type A inclusion bodies. The lesions resolve after 18 days.

• Recurrent Oral herpes HSV: A 22 year old medical student studying for examinations feels a twinge at the crimson border of his lip and 24 hours later has a single vesicular lesion at the site

• Recurrent genital HSV: A sexually active 32 year old woman has a recurrence of ulcerative vaginal lesions with pain, itching, dysuria, and systemic symptoms 48 hours after being exposed to UVB light while skiing. The lesion resolves within 8 days. Results of a Papanicolaou smear shows multinucleated giant cells (synctyia) and Cowdry type A inclusion bodies

• Encephalitis HSV : A patient has focal neurologic symptoms and seizures. Magnetic resonance imaging results show destruction of a temporal lobe. Erythrocytes are present in the CSF and PCR is positive for viral DNA

• Varicella (chickenpox): A 5 year old boy develops a fever and maculopapular rash on his abdomen 14 days after meeting with his cousin, who also developed the rash. Successive crops of lesions appeared for 3 to 5 days and the rash spread peripherally

• Zoster (shingles): A 65-year old woman has a belt of vesicles along the thoracic dermatome and experiences severe pain localized in the region

• Infectious mononucleosis (EBV) : A 23- year old college student develops malaise, fatigue, fever, swollen glands, and pharyngitis. After empirical treatment with ampicillin for sore throat, a rash appears. Heterophile antibody and atypical lymphocytes were detected in the blood.

• Congenital CMV disease: A neonate exhibits microcephaly, hepatosplenomegaly,a dn rash. Intracerebral calcification is noted on the radiograph. The mother had symptoms similar to mononucleosis during the third trimester of her pregnancy.

• Roseola (exanthema subitum) Human Herpes Virus 6: A 4 year old child experiences a rapid onset of high fever that lasts for 3 days and then suddenly returns to normal. Two days later, a maculopapular rash appears on the trunk and spreads to other parts of the body.

Case studies and Questions Page 563

A 2-year-old child with fever for 2 days has not been eating and has been crying often. On examination the physician notes that the mucous membranes of the mouth are covered with numerous shallow, pale ulcerations. A few red papules and blisters are also observed around the border of the lips. The symptoms worsen over the next 5 days and then slowly resolve, with complete healing after 2 weeks.

The physician suspects that this is an HSV infection. How would the diagnosis be confirmed?

The diagnosis can be confirmed by taking a Tzanck smear and analyzing the cells taken from the base of a lesion for syncytia and Cowdry type A inclusion bodies. The sample can also be analyzed by immunofluorescence. A sample of vesicle fluid can be put into cell culture and observed for characteristic cytopathological effects or analyzed by PCR for the HSV genome

•

How could you determine whether this infection was caused by HSV-1 or HSV-2?

Immunofluorescence using type-specific antibodies or PCR analysis of the samples indicated in question 1 can distinguish HSV-1 from HSV-2.

•

What immune responses were most helpful in resolving this infection, and when were they activated?

Innate responses, such as interferon-∀a, and NK cells are activated early to limit the spread of virus followed later by T cell responses and antibody. T cells are essential for resolution of infection, but antibody assists in the cleanup of the infection, although it is not sufficient for protection

•

HSV escapes complete immune resolution by causing latent and recurrent infections. What was the site of latency in this child, and what might promote future recurrences?

Latency is established in the trigeminal ganglia. Future recurrences will be triggered by stresses such as UVB light and emotional or physical stress.

•

What were the most probable means by which the child was infected with HSV?

•

|The child was infected by contact with an infected person or by sharing an item with someone bearing an active |

|lesion. |

Which antiviral drugs are available for the treatment of HSV infections? What are their targets? Were they indicated for this child? If not, why not?

|Most of the effective anti-HSV drugs are nucleotide analogues, which are activated by the viral-encoded |

|thymidine kinase and then will inhibit the viral DNA-dependent DNA polymerase. These drugs include |

|valacyclovir, acyclovir, penciclovir, and famciclovir. They are not indicated for this child because the |

|infection is not life-threatening and the disease has progressed beyond the time within which the drugs would |

|be effective. |

A 17-year-old high school student has had low-grade fever and malaise for several days, followed by sore throat, swollen cervical lymph nodes, and increasing fatigue. The patient also notes some discomfort in the left upper quadrant of the abdomen. The sore throat, lymphadenopathy, and fever gradually resolve over the next 2 weeks, but the patient's full energy level does not return for another 6 weeks.

•

What laboratory tests would confirm the diagnosis of EBV-induced infectious mononucleosis and distinguish it from CMV infection?

The most simple test would be a heterophile antibody test, which is specific for EBV and not CMV. Serology for EBV antigens could confirm the diagnosis. These tests will also distinguish between a current and previous course of EBV disease.

•

To what characteristic diagnostic feature of the disease does mononucleosis refer?

|The mononucleosis results from the expansion in numbers of T cells upon stimulation by the EBV-infected B |

|cells. Mononucleosis-like syndromes accompany other infections of lymphocytes including CMV and HIV. |

|What causes the swollen glands and fatigue? |

| |

|Swollen glands and fatigue are caused by the large scale activation of the immune response as indicated by the |

|expansion of the numbers of T cells. |

| |

|Who is at greatest risk for a serious outcome of an EBV infection? What is the outcome? Why? |

|Immunocompromised individuals are at risk for EBV-induced leukemia and lymphoma-like diseases because |

|EBV-stimulated B cells will grow out of control in the absence of functional T cells. Boys with Duncan's |

|disease (X-linked immunodeficiency) die of leukemia-like immunoproliferation caused by the inability of their T|

|cells to control the outgrowth of B cells (this function is normally used to limit the outgrowth of B cells in |

|response to antigen). |

| |

Chapter 65: Retroviruses

• Boxes 65-1, -2, -3, - 4 (only category headings for box 65-4)

• Figure 65-5 (replication mechanism)

• Figure 65-6 and the associated paragraph of “replication” section (paragraph starts on bottom of page 659 and proceeds onto page 660)

• Figures 65-8 and 65-9

• Table 65-5

• Section on “treatment, prevention, and control” on page 670

Box 65-1 Unique Characteristics of Retroviruses

*Virus has an enveloped spherical virion that is 80-120 nm in diameter and encloses a capsid containing two copies of the positive strand RNA genome

*RNA-dependent DNA polymerase (reverse transcriptase) and integrase enzymes are carried in the virion

*Virus receptor is the initial determinant of tissue tropism

*Replication proceeds through a DNA intermediate, termed the provirus

*The provirus integrates randomly into the host chromosome and becomes a cellular gene

*Transcription of the genome is regulated by the interaction of host transcription factors with promoter and enhancer elements in the long-terminal repeat (LTR) portion of the genome

*Simple retroviruses encode gag ( for capsid, matrix, and nucleic acid binding proteins), pol ( for polymerase, protease ,and integrase), and env ( for envelope) genes which all encode polyproteins for the enzymatic and structural proteins. Complex retroviruses also encode accessory genes (tat, rev, nef, vif, vpu for HIV)

* p17gag is important for the budding process

* Viral glycoproteins are produced by proteolytic cleavage of the polyprotein encoded by the env gene.

*Virus assembles and buds from the plasma membrane

*Final morphogenesis of HIV requires proteases, cleavage of gag and gag-pol polypeptides after envelopement

Figure 65-5 Replication Mechanism

*Replication of the human retroviruses (HIV and HTLV) starts with binding of the viral glycoprotein spikes (trimer of gp120 and gp41 molecules) to the CD4 protein, the primary receptor and other chemokine receptors and enters by fusion. For newly transmittd HIV, the gp120 binds to the CD4 protein on cells of macrophage lineage and activated T cells.

* The genome is reverse transcribed into DNA in the cytoplasm and integrated into the nuclear DNA. The reverse transcriptase encoded by the pol gene uses the tRNA in the virion as a primer and synthesizes a complementary, negative strand DNA (cDNA). Transcription and translation of the genome occur in a fashion similar to that of human T-lymphotropic virus (HTLV-1).

*During the synthesis of the virion DNA (provirus), sequences from each end of the genome (U3 and U5) are duplicated, thus attaching the LTRs to both ends creating sequences necessary for integration and enhancer and promoter sequences within the LTR fro the regulation of transcription. The DNA copy of the genome is larger than the original RNA

*The double stranded cDNA is then delivered to the nucleus and spliced into the host chromosome with the aid of a virus encoded, virion carried enzyme, integrase

* Once integrated, the late phase begins and viral DNA is transcribed as a cellular gene by the host RNA polymerase II. Transcription of the genome produces a full-length RNA, which for simple retroviruses is processed to produce several mRNAs that contain either the gag,gag-pol, or env gene sequences.

*The ability of the cell to transcribe the retroviral genome is the 2nd major determinant of tissue tropism and host range for a retrovirus.

*The proteins translated from the gag,gag-pol and env mRNAs are synthesized as polyprotein and are subsequently cleaved to functional proteins. Glycoproteins are processed by the ER and Golgi and cleaved into membrane spanning subunits of the viral attachment protein to form trimers on the plasma membrane

* The association of two copies of the genome and cellular transfer RNA molecules promotes budding of the virion. The protease step is required for the production of infectious virions

*Envelopment and release occur at the cell surface and can also spread from cell to cell through the production of syncytia.

*Since reverse transcriptase is very error prone, it is responsible for promoting the generation of new strains of virus during a person’s disease, a property that may alter the pathogenicity of the virus and promote immune escape.

Figure 65-6 Target cell Binding of HIV

*Variants of HIV bind to CD4 and a different chemokine receptor (CXCR4) on naïve and other helper T cells. Chemokines are small peptides involved in promoting inflammatory reactions and chemotaxis. People resistant to infection are genetically deficient of these coreceptors.

* Binding to the chemokine receptor brings the viral envelope and cell plasma membrane closer together and allows the gp41 to interact with and promote fusion of the two membranes.

* The fusion step is the target for an antiviral drug that interferes with the action of gp41.

Box 65-2 Disease Mechanisms of HIV

• HIV primarily infects CD4 T cells and cells of the macrophage lineage (monocytes, macrophages, alveolar macrophages of the lung, dendritic cells of the skin, and microglial cells of the brain)

• Virus causes lytic infection of CD4 T cells and persistent low level productive infection of macrophage lineage cells

• Virus causes syncytia formation, with cells expressing large amounts of CD4 antigen (T cells) with subsequent lysis of the cells

• Virus alters T-cell and macrophage cell function

Figure 65-8 Pathogenesis of HIV

*HIV causes lytic and latent infection of CD4 T cells and persistent infection of cells of the monocyte macrophage family and disrupts neurons. The outcomes of these actions are immunodeficiency and AIDS.

*The macrophage reservoir can cause dysfunction, virus release, and cytokine release and dysregulation fo immune functions

*Continuous replication of the virus occurs in the lymph nodes, with subsequent release of the virus and infected T cells into the blood leading to AIDS and dementia

*Immunodeficiency, loss of B cell control, lymphadenopathy, hypergammaglobulinemia, loss of DTH function can lead to severe systemic opportunistic infections, Kaposi’s sarcoma, and lymphoma

Figure 65-9 Time course and stages of HIV

*A long clinical latency period follows the initial mononucleosis like symptoms.

* The progressive decrease in the number of CD4 T cells, even during the latency period, allows opportunistic infections to occur. The stages of HIV disease are defined by the CD4 T cell levels and occurrence of opportunistic diseases

* A significant drop in T cell number occurs after the acute infection

*The virus may seroconvert as time progresses from the initial infection so can see an increase in T cell number after 60 months

*AIDS, dementia occur after 60 months

*anti-HIV antibody increase in stage 1 and 2 and then decrease in stage 3

Box 65-3 Epidemiology of HIV

Disease/Viral Factors

• Enveloped virus is easily inactivated and must be transmitted in body fluids

• Disease has a long prodromal period

• Virus can be shed before development of identifiable symptoms

Transmission

• Virus is present in blood, semen, and vaginal secretions. Not through coughing, kissing, touching.

Who is at Risk?

• Intravenous drug abusers, sexually active people with many partners (homosexual and heterosexual); prostitutes, newborns of HIV-positive mothers

• Blood and organ transplant recipients and hemophiliacs before the 1985 screening programs

Geography/ Season

• There is an expanding epidemic worldwide

• There is no seasonal incidence

• HIV I seen in America and western countries; HIV II seen in west Africa

Modes of Control

• Antiviral drugs limit progression of disease

• Vaccines for prevention and treatment are in trials

• Safe, monogamous sex helps limit spread

• Sterile injection needles should be used

• Large-scale screening programs for blood for transfusions, organs for transplants, and clotting factors used by hemophiliacs

Box 65-4 Potential Antiviral Therapies for HIV Infection

• Nucleoside Analogue Reverse Transcriptase Inhibitors- phosphorylated by cellular enzymes and are incorporated into cDNA to cause DNA chain termination

• Non-nucleoside Reverse Transcriptase Inhibitors – inhibit the enzyme by other mechanisms

• Protease inhibitors – block the morphogenesis of the virion by inhibiting the cleavage of the gag and gag-pol polyproteins

• Fusion inhibitors

• Highly Active Antiretroviral Therapy (HAART) combination of AZT, 3TC, protease inhibitor)

Table 65-5 Indicator Diseases of AIDS

|Infection |Disease |

|Opportunistic Infections | |

|Protozoal |Toxoplasmosis of the brain |

| |Cryptosporidiosis with diarrhea |

| |Isosproiasis with diarrhea |

| Fungal |Candidiasis of the esophagus, trachea and lungs |

| |Pneumocytis jiroveci pneumonia |

| |Cyptococcosis |

| |Histoplasmosis |

| |Coccidioidomycosis |

| Viral |CMV disease |

| |HSV infection |

| |Progressive multifocal leukoencephalopathy |

| |Hairy leukoplakia caused by EBV |

| Bacterial |Mycobacterium avium intracellularae complex |

| |Any “atypical” mycobacterial disease |

| |Extrapulmonary TB |

| |Salmonella septicemia |

| |Pyogenic bacterial infections |

|Opportunistic neoplasia (cancers) |Kaposi’s sarcoma |

| |Primary lymphoma of the brain |

| |Other non-Hodgkin’s lymphoma |

|Others |HIV wasting syndrome |

| |HIV encephalopathy |

| |Lymphoid interstitial pneumonia |

Treatmemt Prevention and Control (Page 670)

*AZT (Azidothymidine) is the recommended treatment of asymptomatic or mildly symptomatic people with CD4 counts of less than 500 and for the treatment of infected pregnant women to reduce likelihood of transmission to the fetus

*HART has less potential to breed resistance and has become recommended. Multidrug therapy can reduce blood levels of virus to nearly zero and reduce morbidity and mortality in pts with advanced AIDS.

Chapter 66: Hepatitis viruses

• Introductory section of chapter on page 675

• Tables 66-1, -2

• Boxes 66-1, -2, -3, -5

• Figures 66-4, -5

• HBV “structure” section on page 679

• “Case studies and questions” on page 689

Introductory Section p.675

There are at least 6 Hepatitis viruses (A-E and G)

The basic hepatits symptoms are similar and differ greatly in their structure, mode of replication, mode of transmission and in time course.

*Hepatitis A (HAV) and hepatitis B (HAB) are the classical hepatitis viruses.

*Hepatitis C, G, E, and hepatitis D are called non-A non-B hepatitis (NANBH) viruses

*Each of the hepatitis viruses infects and damages the liver, causing the classic icteric symptoms of jaundice and the release of liver enzymes. The specific virus causing the disease can be distinguished by the course, nature, and serology of the disease. These viruses are contagious and spread without even showing symptoms

*Hepatitis A (aka infectious hepatitis), is caused by a picornavirus (RNA virus)

- is spread by the oral-fecal route

- has an incubation period of approximately 1 month after which icteric symptoms start abruptly

-does not cause chronic liver disease

-rarely causes fatal disease

*Hepatitis B (aka serum hepatitis) is caused by a hepadnevirus with a (DNA genome)

-is spread parenterally by blood or needles, by sexual contact, and perinatally

-has a median incubation period of approximately 3 months after which icteric symptoms start insidiously

-is followed by chronic hepatitis in 5% to 10% of patients

-is causally associated with primary hepatocellular carcinoma (PHC)

-more than 1/3 of world infected by HBV resulting in 1-2 million deaths per year

-The incidence is decreasing especially in infants due to development of HBV subunit vaccine.

*Hepatitis C (HCV) is widely prevalent with more than 170 million carriers

-spread by same routes as HBV but usually causes chronic disease

-is a flavivirus with an RNA genome

*Hepatitis G also a flavivirus and causes chronic infections

*Hepatitis E is an enteric virus in the Noravirus family

-disease resembles HAV

*Hepatitis D (delta hepatitis) is unique in that it requires actively replicating HBV as a “helper virus” and occurs only in patients who have active HBV infection

-HBV provides an envelope for HDV RNA and its antigens

-Delta agent exacerbates the symptoms caused by HBV

Figure 66-5 Replication of Hepatitis B virus

First, HBV has a distinctly defined tropism for the liver. HBV replicates through an RNA intermediate and produces and releases antigenic decoy particles (HbsAg).

1) The attachment of HBV to hepatocytes is mediated by the HbsAg glycoproteins. Several liver cell receptors have been suggested including the transferrin receptor, the asialoglycoprotein receptor, and human liver endonexin.

2) HbsAg binds to polymerized human serum albumin and other serum proteins and this interaction may facilitate binding and uptake of the virus by the liver.

3) Uncoating of the nucleocapsid core occurs and on penetration into the cell, enzymes in the core cause the partial DNA strand of the genome to be completed by being formed into a complete double stranded DNA circle and the genome is delivered to the nucleus.

4) Transcription of the genome is controlled by cellular transcription elements found in hepatocytes. DNA is transcribed into three major classes (2100, 2400, and 3500 bases) and two minor classes (900 bases) of overlapping messenger RNAs. The 3500 base mRNA is larger than the genome and encodes the Hbc and Hbe antigens, the polymerase, and a protein primer for DNA replication and acts as a template for replication of the genome. The 900 base mRNA encodes the X protein, which promotes viral replication as a transactivator of transcription and as a protein kinase.

5) The mRNA then moves to the cytoplasm and is translated into protein. Core proteins assemble around the 3500 base mRNA, and negative sense DNA is synthesized by a reverse transcriptase activity in the core containing RNA dependent DNA polymerase and ribonuclease H activity but lacks the integrase activity of the retrovirus enzyme.

6)The 3500 base RNA is larger than the genome and acts as a template and negative-strand DNA is synthesized using a protein primer, which remains covalently attached to the 5 prime end.

7) The RNA is degraded by the ribonuclease H activity as the positive strand DNA is synthesized from the negative sense DNA template. But this process is interrupted by envelopment of the nucleocapsid at HbsAg-containing membranes of the endoplasmic reticulum thereby capturing genomes containing RNA-DNA circles with different lengths of RNA.

8) Continuing degradation of the remainder of the RNA in the virion yields a partly double-stranded DNA genome. The virion is then released from the hepatocyte by exocytosis without killing the cell, and not by cell lysis.

Table 66-1 Comparative Features of Hepatitis Viruses

|Feature |Hep. A |Hep B |Hep C |Hep D |Hep. E |

|Common Name |“infectious” |“serum” |“non-A, non-B |“Delta agent” |“Enteric non-A, |

| | | |post-transfusion” | |non-B” |

|Virus Structure |Picornavirus; capsid,|Hepadnavirus; envelope,|Flavivirus; envelope, |Viroidlike; envelope, |Norovirus; capsid,|

| |RNA |DNA |RNA |circular RNA |RNA |

| |Naked icosahedral | | | | |

| |capsid | | | | |

|Transmission |Fecal-oral |Parenteral, sexual |Parenteral, sexual |Parenteral, sexual |Fecal-oral |

|Onset |Abrupt |Insidious |Insidious |Abrupt |Abrupt |

|Incubation period (days) |15-50 |45-160 |14-180 |15-64 |15-50 |

|Severity |Mild; jaundice |Occasionally severe |Usually subclinical; |Coinfection with HBV |Normal patients, |

| |observed in 70-80% of| |70% chronicity |occasionally severe; |mild; pregnant |

| |adults | | |superinfection with HBV|women severe |

| | | | |often severe | |

|Mortality | ................
................

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