Exam 2 week 2 Flashcards

Question

Describe in detail the interactions of EBV with cells

Answer 1

**1) Replication of EBV in** permissive cells (non-memory, resting B cells in tonsils): EBV infection can cause the synthesize up to 70 viral proteins. **Immediate early, early** **and late phases** of the cell cycle. (See previous herpesvirus lecture) Late proteins **gp350/220** **are glycoproteins** that are located in the viral envelop enable attachment of the to specific receptors on the surface of cells (CD21). B Cell entry via fusion, gp42 interacts with MHC class II molecules to promote fusion. EBV binding to CD 21 initiates the activation and replication of B cells. Expression of certain viral proteins (see full listing above) help maintain the infectious process. Virus replication occurs and progeny virus particles are produced to can be found in high amounts in the infected patient’s saliva. Lytic infection initiates with the immediate early protein, ZEBRA, acting as a transcription factor that furthers the transcription of immediate early genes that then stimulates early gene transcription. Following viral genome synthesis in the nucleus of the infected cell late capsid and envelop proteins are synthesized. Progeny virus is then formed. (The more detailed replication of herpesviruses was covered previously) **2) Latent infections** require a different type of EBV and B cell interactions. The lytic infection (in permissive cells) can give rise to latent infections depending on the differentiation state of B cells. **Memory** B cells are conducive to the formation of latent infections. In latent infections viral genomes circularize and resemble a plasmid. This form of viral DNA replicates in tandem with cell division via cell DNA polymerase. EBNA-1 is important in maintaining latency Therefore, only specific genes are expressed from the circular genome. Viral antigens include **EB Nuclear Antigen-1**, and **latent** **proteins** (**LP**s), both EBNA and LPs are DNA binding proteins). 3) B cell immortalization: _Latent Membrane proteins 3(LMPs)_ **stimulate** **the replication of B cells and promote their immortalization.**

Answer 2

Disease - Infection at early age --no disease, Delayed exposure to virus until adolescence or adulthood causes more severe disease, ie IM Virus found in saliva, eg. spread by kissing; replication in regional lymph nodes and epithelial cells in the respiratory system Infected B lymphocytes transmit virus to other lymph nodes and spleen * Atypical lymphocytes (Downey Cells) in blood correspond to large T lymphocyte that form in response to EBV infected B cells * Some disease symptoms associated with IM result from the immunological attack by T lymphocytesagainst EBV infected B lymphocytes, cytokine production is present * **Synthesis of a IL-10 analog by EBV** during the infection thwarts the TH1 CD4 T cell immunological response three (3) primary symptoms 1. **lymphadenopathy (enlarged lymph nodes/glands),** 2. **splenomegaly (enlarged spleen),and** 3. **exudative pharyngitis** * plus headache, chills, high fever, malaise

Answer 3

Immune Response: Several responses 1. **Heterophile antibodies** - short lived ab - not virus specific; infected B cells differentiate and produce polyclonal antibodies some of which are heterophile and autoantibodies 1. Heterophile Antibodies agglutinate RBCs of non human origin, horse or sheep RBCs 2. 60-80% positive sera for heterophile Ab 2. Specific antibodies to EB virus proteins 3. T lymphocyte response to EBV infected B cells

Answer 4

1) Atypical lymphocytes (T lymphocytes= **Downey cells**), large, basophilic, foamy (vacuolated) cytoplasm 2) Heterophile antibodies (IgM) - "**monospot test**" - patients serum is treated with GP-RBC to remove nonspecific factors ------\> Horse (sheep) RBC-------\> Agglutination = + test; * some sera from patients are **heterophile** **- negative**, must differentiate from heterophile negative CMV mononucleosis, * use antibody detection to VCA (IgM),EA, MA, EBNA 3) Best: virus neutralization, immunofluoresence, CF for viral antibodies 4) Time course VCA (IgM) ---\> VCA (IgG) ----\> EA + EBNA Abs, antibodies peaks few weeks after infection - last for years antibodies for EBNA in combination with VCA (IgG) indicate a past infection

Answer 5

1. Epidemiology and control 1. 90% of adults have antibody 2. Spread orally - large dose required in saliva "Kissing Disease", share toothbrush etc 3. Common in institutions and colleges, asymptomatic primary disease of young children, more severe primary infection for adolescence and adults(college students) 2. Treatment – symptomatic, limited approval antiviral drugs; Valacyclovir for severe cases + steroids 3. Vaccine: Experimental subunit vaccine

Answer 6

**EBV May act as a _cofactor rather than the sole cause_ of malignancies** 1. Infectious mononucleosis 2. Associtaed with **Burkitt's lymphoma (Africa);** * Geographical area **(**africa also where there is malaria) * activation of MYC protooncogenes may cause lymphoma * Development of lymphoblastoid cell lines that grow in tissue culture - EB viral DNA exist as plasmid in cells from EB patient and imparts increased cell growth 3. Associated with **nasopharyngeal carcinoma (china)** **Predilection for B lymphocytes** * ****Possibly Burkitts lymphoma and other types of lymphomas,Hodgkins Infectious mononucleosis (heterophile antibody +)nasopharyngeal carcinoma, gastric cancers,oral hairy leukoplakia in AIDS patients, autoimmune disease links

Answer 7

**EBV May act as a _cofactor rather than the sole cause_ of malignancies** 1) Nasopharyngeal carcinoma 1. Nonlymphoid cells, EB genome present in epithelial cells 2. Males of Chinese extraction Lymphoproliferative disease * If T cell deficiency exists in patient, EBV induces B cell leukemia-like or lymphoma may develop. Shows the importance of T cells keeping EBV infected B cell proliferation in check. 2) Chronic EBV mono - possible association **Fatigue, fever, headaches, mental lapses, numbness and depression, symptoms last months to years** 1. Chronic mononucleosis or chronic viral fatigue syndrome most common, different symptoms per patient, fatigue is common, woman 2X affected compared to men, 1 year average duration 2. Other possible causative agents include Human herpesvirus 6 or a retrovirus

Answer 8

**Roseola i**s caused by **HHV 6 and 7** while **Kaposi’s Sarcoma** involves **HHV 8** **1)** Human herpes virus 6(**HHV6B**); not antigenically related to other herpesviruses: * **Causes Exanthem subitum (roseola)** and infect large numbers of children. * Infects B and T cell (lymphotropic) and can infect epithelial and endothelia cells as well as neurons. * Cause latent infections in T cells and monocytes and can reactivate in transplant patients and immunosuppressed patients. * Found at high levels in saliva as a result of replication in the salivary glands **2) HHV 6 and 7** isolates also **causes roseola** which is characterized by a **high fever (103-105 F)and a disseminated rash** (trunk and face first and then spreads) follows as the fever resides, rash last 24 to 48 hrs **3) HHV 8** has been associated with Kaposi sarcoma and a rare type of B cell lymphoma. B cells are primarily infected by HHV8 but other cell types can be infected. HHV8 encodes proteins with growth factor characteristics and ability to slow apoptosis of infected and uninfected cells, eg. Interleukin-6 homolog * Kaposi sarcoma found at elevated levels in AIDS patients.

Answer 9

**HI****V - Virus Structure** -- basically similar to other retroviruses, especially other Lentiviruses. * It is considered to be a complex retrovirus and has genome that possesses genes in addition to gag,pol and env genes, which found in the genomes of the simpler retroviruses. The additional genes are TAT, REV, VIF, NEF and VPU, and VPR, all of which encode **accessory proteins** that seem to play a regulatory role during HIV infection. **Review**: GAG proteins are the core and capsid structural proteins * POL proteins are part of a enzymatic complex which includes reverse transcriptase, DNA polymerase, RNAse H, protease and integrase * ENV proteins constitute the spikes on the envelop of the virus, gp 160 = gp120 + gp 41

Answer 10

Accessory Genes encode Accessory Proteins * **TAT** = Transcription Transactivator for **both** viral and cellular control regions of genes, ( Remember from our previous discussion of retroviruses that the LTRs located at each end of the provirus has promoters and enhancers that bind regulatory proteins such as TAT) * **REV** = Regulates transport of viral mRNAs out of the nucleus and into the cytoplasm, also regulates splicing of viral RNAs that leads to the formation of viral mRNAs * **NEF** = Diminishes the expression of CD4 and MHC 1 which changes T cell signaling and is required to achieve a high virus load. NEF is a **key** component in enabling a limited HIV infection to progress to full blown HIV replication. * **VIF** promotes virus assembly and blocks the action of a cellular protein (APOBEC-3G) that normally acts as an antiviral protein * **VPU** enhances the release of virus from infected cells and inhibits the cell surface expression of CD4 on infected cells * **VPR** arrests infected cells in G2 phase of cell cycle, which is optimal phase for HIV replication and enhances the transport of proviral DNA (provirus) from the cytoplasm into the nucleus

Answer 11

1. Genomic RNA exists in two identical copies in direct association with two proteins; p 9, p 7. 2. Genome RNA is housed within a **cylindrical core** composed of p24 - reverse transcriptase is located inside core. 3. An outer envelope surrounds core. Underlying the envelope is a layer of p 17 protein. 4. The envelope possesses glycoprotein spikes extending outward from its surface. Each spike is composed of 3 or 4 identical polypeptides, each polypeptide is designated gp 160. (glycoprotein 160,000 mw) 5. Each gp 160 is usually proteolytically cleaved into two subunits; distal gp 120 (gp 120,000 mw) and proximal gp41. 6. gp 120 and gp 41 are held together by noncovalent bonds. 7. **gp 160 and gp 120-gp41 are the major antigens of the virus**, which change antigenically within a given population or even in a particular individual infected with the virus (see M tropic àT tropic HIV above) 8. gp 120 important for attachment of virus to receptor on cell surface. **_gp41_ possess amino acid sequence necessary for viral envelope _fusion_ with cell membranes or fusion between an infected cell and uninfected cells**. (Remember the HA protein of influenza virus and its role in cell membrane- envelop fusion)

Answer 12

HIV provirus: Diagram **below** is not drawn to scale and represents the proviral form derived from the viral genome. LTR = Long terminal repeat located at each end of the provirus Note: TAT and REV mRNA are synthesized as a result of multiple splicing events. Segments 1 + 2 + 3 = mRNA; 1,2, and 3 represent different sequences for TAT and REV Recombination (copy choice) between two copies of genomic RNA is a source of genetic variation in addition to variations caused by point mutations. Reverse transcriptase can jump from on 35S RNA to another to yield the final form of the provirus. May be a mechanism to repair breaks in the template genomic RNAs when it is copied into a provirus. Recombinational changes assume that the two genomic copies within a virus vary in ribonucleotide sequence and are not the same.

Answer 13

1. Cells that are infected by HIV vary depending on the specificity between gp 120 and the receptor/co receptor (chemokine receptors CCR5 and CXCR4) 2. HIV attaches to cells which possess CD4 molecules on their surfaces, eg. T lymphocytes, macrophages and certain brain cells (microglial cells). 3. In addition to the CD4 receptor, a second molecule (coreceptor) is involved in the binding and fusion of the virus with the cell. The copreceptor may be one of two types; CC**R****5**coreceptor is present on the surface of certain peripheral T cells/macrophage and HIV strains that bind to these cells is designated**M Tropic** HIV. 4. Other HIV strains bind to cells using CD4 and the C**X**CR**4** coreceptor, which is present on the surface of the majority of T cells (**T Tropic HIV**) (some individuals lack CCR5 and are resistant to HIV infection) As indicated above, the M Tropic (**R5**) HIV usually is the type that initiates HIV infections. As a result of mutations in the gp120 viral glycoprotein gene, the virus changes to T Tropic(**X4**) as the HIV infection progresses into the immunosuppressive state.

Answer 14

5. Following uncoating, genomic RNA is reverse transcribed into a provirus which moves to the nucleus where it is integrated into cell DNA. 6. Once the provirus is integrated into cell DNA it becomes transcriptionally active. A variety of mRNAs are formed that encode the proteins of the virus and the accessory proteins 7. Viral RNA are spliced once or twice depending on the RNA, mRNAs for REV and TAT are spliced twice (See diagram) 8. The immature virus buds and to acquire its envelop and the GAG and POL polyproteins located within the immature virus particle are cleaved and a mature virus particle results 9. **Kaposi's sarcoma and other malignancies are induced during HIV infection.** How can a tumor form without an oncogene? **_TAT_** seems to play a role as a transactivator and is released from HIV infected cells to induce the sarcoma ( TAT gene was introduced into transgenic mice and the expression of this gene induced a malignancy similar to Kaposi's sarcoma) HHV-8 has been implicated at the primary causative agent for Kaposi’s sarcoma (see end of previous lecture on CMV and EBV)

Answer 15

attachment, provirus formation, proteolytic cleavage of viral polyproteins, and budding are some of these targets.

Answer 16

1. HIV infection diagnostics: Detection of HIV specific antigens and _antibodie__s_ specific for HIV proteins; screened in human serum. 2. CDC/APHL algorithm which includes antigen-antibody combination assay as part of a screening process to detect HIV infections; 1 out of 1,000 to 3000 yield false positive results A few examples: Abbott Architect HIV Ag/Ab Combo, Bio-Rad GS HIV Combo, Siemens Advia Centaur HIV AG/Ab Combo, etc. Based on immunoassays 3. If combo test is positive an antibody test can differentiate between HIV-1 and HIV-2, Again an immunoassay, Bio-RAD Geenius HIV 1/2 Assay 4. If discrepant results are found between initial antigen- antibody screen and the HIV 1/2 Assay then a nucleic acid test, Hologic Aptima HIV-1RNA Qualitative Assay, is employed Positive RNA test indicates acute HIV infection 5. Nucleic acid testing is based on Reverse Transcriptase (RT) PCR is used to determine the HIV load in blood. This is reported in RNA copies per ml and is used as an indicator of the extent of HIV replication. 6. HIV genomes can be sequenced to detect specific mutations in viral genes that encode key enzymes, such as Reverse Transcriptase. The mutations have been shown to impart drug resistance to HIV, such as resistance to reverse trans- scriptase inhibitors.

Answer 17

* Confirmatory test (picture below); Test for antibodies for presence of HIV viral proteins * Detection of HIV specific antigens and **_antibodie__s_** specific for HIV proteins; screened in human serum. * Presumptive test * OraQuick Advance HIV (1/2); fingerstick whole blood, oral fluid; moderate complexity with plasma. Result in 20 minutes. Screens for HIV 1 and HIV 2. Store at room temp. * Collect oral fluid specimens by swabbing gums with test device

Answer 18

* •Immune System & CNS * •Immune System * •Profound immunodeficiency * •Affects cell-mediated immunity * Cell populations infected * CD4+ T cells; few affect in blood but large numbers affected in lymph node. CD4+ T cells are depleted * Monocytes/macrophages * Dendritic cells

Answer 19

* •Activation-induced apoptosis * •Non-cytopathic HIV infection * •Activates inflammasome pathway * •Cell death due to pyroptosis * •Cytokines and other cell contents are released and recruit new cells for possible infection * •Destruction of architecture of lymphoid organs * •Loss of immature precursors * •Thymic progenitor cells are infected * •Infection of accessory cells * •Syncytia formation * Fusion of uninfected & infected

Answer 20

**_Qualitative_** defect of CD4+ T cells (seen in asyptomatic patients) * •Reduction in antigen-induced T cell proliferation * •Decrease in TH1 type responses relative to TH2 type * •Increased susceptibility to infection by viruses * •Marked decrease in cell-mediated immunity * •Loss of memory T cells – poor recall function * •Decreased helper function for B cell antibody production * •All defects can be seen even in asymptomatic HIV-infected individuals

Answer 21

Latent infection; Important feature of HIV infection * •Latent virus is found in CD4+ T cells and macrophages in lymph nodes * •Protected from antiviral therapy * •Provides a persistent reservoir of virus **Monocytes/Macrophages** * •10-50% of macrophages in tissue are infected, many more than are monocytes in blood * •Infected macrophages bud few viruses from the cell surface, store large numbers of viral particles, allow replication but are quite resistant to cytopathic effects * •Relatively protected from host defenses * Serve as reservoirs of infection and virus factories later in infection when CD4+ T cell counts are low * •Play an important role in CNS infections – HIV is carried into brain by infected monocytes * •Abnormalities in function * – Decreased phagocytosis & chemotaxia * – Decreased secretion of IL-1 * – Decreased ability to present antigens to T cells * •Certain HIV strains are tropic for macrophages

Answer 22

* •**Mucosal** dendritic cells * •Initially infected by virus * •Transport virus to lymph nodes where virus is transferred to CD4+ T cells * **•Follicular** dendritic cells (in germinal centers) * •Reservoirs of infection & trap virions

Answer 23

* •Polyclonal activation with germinal center B cell hyperplasia * •Bone marrow plasmacytosis * **•Hypergammaglobulinemias** * •Increased circulating immune complexes * •Inability to mount Ab response to new Ag * •Impaired humoral immunity renders patients vulnerable to disseminated infections caused by encapsulated bacteria

Answer 24

HIV with CNS involvement 1. Nervous system is a major target of HIV infection 2. Macrophages and microglia are predominant cell types infected 3. HIV is carried into brain by infected monocytes but neurons are not infected 4. Actual mechanisms of damage are not clear but most likely caused indirectly by viral products and other factors, such as cytokines (IL-1, TNF, IL-6)

Answer 25

* T cell * CD4+ T cell quantitative defect/depletion * CD4 T cell qualitative defect * Non T cell * Monocytes/macrophages * Dendritic cell (mucosal and follicular) * B lymphocytes

Answer 26

* Primary infection * Virus dissemination * Acute retroviral syndrome * Chronic infection, phase of clinical latency * T cell going down and virus going up \ * oppurtunistic infection (candidiasis) * AIDS

Answer 27

Primary infection, virus dissemination and acute retroviral syndrome: 1. Virus typically enters through mucosal epithelia 2. Early infection is characterized by infection of memory CD4+ T cells in mucosal lymphoid tissue with death of many infected cells 3. Next step is dissemination to lymph nodes by infected dendritic cells 4. In lymph nodes, virus may pass to CD4+ T cells by direct cell-cell contact 5. Replication in lymph nodes leads to viremia with high numbers of HIV particles in the blood 6. Infected individual mounts antiviral humoral and cell-mediated immune responses evidenced by seroconversion, usually 3 to 7 weeeks after exposure, which correspond to drop in serum viral titers 7. Acute retroviral syndrome * a. Develops in ~40-90% of patients * b. Typically 3-6 weeks after infection; resolves in 2-4 weeks * c. Nonspecific symptoms of sore throat, myalgias, fever/sweats, weight loss, fatigue * d. Also, rash, cervical adenopathy, diarrhea, vomiting

Answer 28

Acute retroviral syndrome \*\*Primary HIV infection

Answer 29

1. Lymph nodes & spleen are sites of continuous HIV replication & cell destruction 2. Few or no clinical symptoms 3. Smoldering destruction of CD4+ T cells in lymphoid tissues 4. Number of CD4+ T cells in peripheral blood slowly declines 5. Host defenses start to decrease; viral burden and number of infected CD4+ T cells increases 6. Patients may be asymptomatic or demonstrate minor opportunistic infections such as candidiasis, herpes zoster, mycobacterial tuberculosis. 7. Typically lasts 7-10 years, but there are exceptions known as rapid progressors and long-term nonprogressors

Answer 30

The criteria for diagnosis of AIDS have been defined by the CDC * a. Certain opportunistic infections and cancers (AIDS-defining opportunistic infections) * b. CD4+ T cell count \< 200 cells/microliter 2. Typically present with fatigue, weight loss, and diarrhea 3. Opportunistic infections account for the majority of deaths in untreated patients with AIDS 4. Many represent reactivation of a latent infection which was kept in check by a normal immune system 4. Many of the opportunistic infections have decreased since the introduction of combination antiviral therapy 5. The most common opportunistic infections include: * Pneumocystic jiroveci pneumonia * Candidiasis * Cytomegalovirus * Mycobacteria * Cryptococcus * JC virus * HSV * Persistent diarrhea * Cancers; Karposi, High grade B cell lymphoma, High risk cervical dysplasia

Answer 31

* a. Pneumocystis jiroveci pneumonia – frequent opportunistic infection; make dx by finding organism in cytologic specimen or biopsy * b. Candidiasis – most common fungal infection; commonly infects oral cavity, vagina, esophagus. Invasive infection is uncommon * c. Cytomegalovirus – may cause disseminated disease, more commonly affects eye (chorioretinitis, may cause blindness) and gastrointestinal tract (esophagitis, colitis) * d. Mycobacteria: Mycobacterium avium-intracellulare disease, disseminated Mycobacterium tuberculosis infection – frequent in AIDS; appearance of M. tuberculosis is similar to non-AIDS, more extensive disease; MAC more unique to AIDS, involves mainly lymph nodes, spleen, liver, marrow, less likely to produce visible granulomas * e. Cryptococcus – meningitis is major clinical manifestation * f. Toxoplasmosis gondii – encephalitis and cerebral abscess * g. JC virus – human papovavirus: progressive multifocal leukoencephalopathy (PML)

Answer 32

* h. Herpes simplex virus – mucocutaneous ulcerations involving the mouth, esophagus,external genitalia and perianal region * j. Persistent diarrhea – caused by any number of protozoal and bacterial infections: Cryptosporidium, Isospora belli, microsporidia, Salmonella, Shigella, M. avium-intracellulare * k. Cancers – AIDS patients have a high incidence of certain cancers, a common feature is they are all caused by oncogenic DNA viruses * **1) Kaposi’s sarcoma** is the most common cancer in AIDS patients. * a) Normally uncommon vascular neoplasm in the US * b) At onset of AIDS epidemic, up to 30% of patients had this * c) With use of new AIDS therapy, incidence \< 1% * d) Can present as purple skin lesions or as disseminated disease in lymph nodes, skin, gastrointestinal tract, or lungs * e) Thought to be due to herpes virus 8 (HHV 8) which is sexually transmitted * f) Immunosuppression is co-factor * **2) High-grade B cell lymphomas** * a) See development of high-grade B cell lymphomas _late in disease course_; occurs in peripheral lymph nodes, brain or body cavites * b) With lower CD 4 counts, see increased risk * c) Associated with Epstein-Barr virus (EBV) * **3) High risk of cervical dysplasia** in women and anal cancer in men – associated with human papillomavirus (HPV) infection

Answer 33

AIDS in the CNS: * 40-60% of patients have clinical involvement in CNS, * 90% at autopsy. * See variety of diseases: aseptic meningitis, peripheral neuropathy, AIDS-dementia complex

Answer 34

Effect of antiretroviral drug therapy – **Highly active antiretroviral therapy _(HAART)_ or combination antiretroviral therapy** * 1. In motivated, compliant patients, HIV replication is reduced below the level of detection and remains there indefinitely * 2. Annual death rate in US reduced from peak of 16-18/100,000 people in 1995-96 to \< 4/100,000 * 3. Long-term side-effects of antiretroviral therapy * a. Lipoatrophy (loss of facial fat * b. Excess fat deposition centrally * c. Premature cardiovascular, kidney and liver disease (major cause of morbidity in AIDS patients

Answer 35

* 1. In general, no specific anatomic changes are present in HIV/AIDS * 2. Lesions are characteristic of opportunistic infections or other processes * 3. Lymph nodes: * a. Marked **follicular hyperplasia** seen early in disease and due to polyclonal B cell activation * b. Later in disease see **follicular involution** – follicles are depleted of cells and the organized network of follicular dendritic cells is disrupted * c. Leads to release of trapped virus; overall small “burnt-out” lymph nodes; spleen and thymus are also affected in this way.

Answer 36

1. Rapid HIV test 2. Antibody studies 3. CD4+ T cell counts 4. Level of HIV-1 RNA is important (viral load test) 5. CDC algorithm for HIV diagnostic testing recommendations (June 2014)

Answer 37

**Rapid HIV test** * **_Look for antigen - antibodies_** * **_If test come back positive, then identify HIV 1 vs HIV 2_**

Answer 38

Antibody studies: 1. Antibodies to HIV appear as early as 6 days to 1 month after acute infection 2. The majority of individuals appear to develop antibodies within 3 months, with rare seroconversion occurring up to 6 months.

Answer 39

CD 4+ T cell counts: 1. Absolute levels of CD4+ cells are of prognostic value, as disease severity usually increases as CD4 counts decrease. 2. Also serve as **reliable short-term indicator of disease progression.** 3. CDC classifies patient into categories based upon CD4 counts, along with other clinical criteria. **Definition of AIDS: CD4+ count of \< 200 cells/microliter**

Answer 40

Level of HIV-1 RNA is important **(viral load test).** * Viral load increase with HIV (no management) * Viral load decrease as HIV is controlled.

Answer 41

**CDC algorithm for HIV diagnostic testing recommendations (June 2014)** * 1. Diagnosis starts with a fourth-generation test that detects HIV in the blood earlier than antibody tests can; it identifies the viral protein HIV-1 p24 antigen, which appears in the blood before antibodies do * 2. If this test is positive, an immunoassay that differentiates HIV-1 from HIV-2 antibodies should be performed; results from such assays can be obtained faster than they can from the Western blot test * 3. In patients with positive results on the initial antigen test but with negative or indeterminate results on the antibody differentiation assay, HIV-1 nucleic acid testing should be performed to determine whether infection is present

Answer 42

HIV Medications review * Screen for HLA-B\*5701 * **Abacavir (ABC) -** NRTI * Bone Marrow Suppression * **Zidovudine (AZT, ZDV) -** NRTI * Pigmentation * Nail = **Zidovudine** * Skin = **Emtricitabine -**NRTI * Pancreatitis * **Didanosine** - NRTI * Peripheral Neuropathy * **Didanosine, Stavudine -** NRTI \*\*\*All these drugs are NRTI; NRTIs are faulty versions of building blocks that HIV needs to make more copies of itself. When HIV uses an NRTI instead of a normal building block, reproduction of the virus is stalled.

Answer 43

* Rash * **Delvaridine, Efavirenz, Etravirine, Nevirapine (NNRTIs) - RASH RASH RASH** * Steven Johnson Syndrome (although rare) highest incidence with Nevirapine * ****RASHES frequently occur within the first 2-4 weeks of therapy Lactic acidosis with hepatic steatosis * **Tenofovir** * All NRTIs; **(Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zidovudine)** * Do Not Start if CD4 \>250 (Woman)/\>400 (Men) * **Nevirapine** * Lipid Abnormalities * **Protease Inhibitors**; (Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir)

Answer 44

* Cross sensitivity with Sulfa Rash (good for PI resistant virus) * **Darunavir, Tipranivir** * Hyperbilirubinemia leading to jaundice * **Atazanavir, Indinavir** * Paresthesias * **Fosamprenavir, Ritonavir** * Booster antiviral * **Ritonavir** * **New booster (no antiviral acivity): cobicistat** * Nephrolithiasis * **Indinvavir**

Answer 45

* Avoid in Pregnancy * **Nelfinavir** * Insulin Resistance/Diabetes Mellitus * **Protease Inhibitors;** (Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir)

Answer 46

* Injection site reaction/irritation * **Enfuvirtide** * Restricted to patients with CCR5 tropic virus * **Maraviroc** * Restricted to treatment experienced HIV patients and causes CPK elevation/pyrexia * **Raltegravir**

Answer 47

Categories of antiretrovirals * CCR5 Antagonist * **Entry inhibitors (Maraviroc)** * Fusion Inhibitors * Fusion inhibitors work by **blocking HIV entry into cells (Enfuvirtide)** * Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) * NNRTIs **bind to and disable reverse transcriptase**, a protein that HIV needs to make more copies of itself * **§Delavirdine (DLV) § Efavirenz (EFV) § Etravirine (ETR) § Nevirapine (NVP) § Rilpivirine (RPV)** * Nucleoside Reverse Transcriptase Inhibitors (NRTIs) * NRTIs are faulty versions of building blocks that HIV needs to make more copies of itself. When HIV uses an NRTI instead of a normal building block, reproduction of the virus is stalled. * **§Abacavir (ABC) § Didanosine (ddI) § Emtricitabine (FTC) § Lamivudine (3TC) § Stavudine (d4T) § Tenofovir (TDF) § Zidovudine (AZT, ZDV)** * Integrase Inhibitors **(Raltegravir, Elvitegravir, Dolutegravir)** * Protease Inhibitors (PIs) * PIs disable protease, a protein that HIV needs to make more copies of itself * **§Atazanavir (ATV) § Darunavir (DRV) § Fosamprenavir (FPV) § Indinavir (IDV) § Lopinavir (LPV) § Nelfinavir (NFV) § Ritonavir (RTV) § Saquinavir (SQV), Tipranavir (TPV)**

Answer 48

Step 1: **Binding** HIV attaches itself to the CD4 receptor of the T4 cell. **{CCR5 antagonist}** Step 2: The HIV cell **fuses** to the outside of the cell {**Fusion Inhibitor}** Step 3: **Reverse Transcription HIV** carries 2 strands of RNA which are released after the binding process. The viral enzyme reverse transcriptase allows the RNA to make a DNA copy, so called the “proviral DNA”. **{NNRTI, NRTI}** Step 4: **Integration** HIV DNA is carried into the host’s nucleus, where the viral enzyme integrase hides proviral DNA until the cell wants to make more proteins, thus making more HIV. **{Integrase inhibitors}** Step 5: **Transcription** Viral DNA separate and special enzymes make complementary mRNA. Step 6: **Translation** mRNA is processed & corresponding strand of HIV proteins are made. Step 7: **Viral Assembly and Maturation** Long strands of viral proteins are cut up by protease into smaller proteins that serve as enzymes or elements of new HIV. Once new HIV is assembled, they bud off and create a new virus. {Protease Inhibitors}

Answer 49

* Reduce HIV related morbidity and prolong survival * Improve quality of life * Restore and preserve immunologic function * Maximally and durably suppress HIV viral load * Prevent vertical HIV transmission

Answer 50

Uncontrolled HIV; increased viral load, decreased CD4 count Controlled HIV; decreased viral load, increased CD4 count * CD4 T Cell Count * Major clinical indicator of immunocompetence in HIV infections * Usually the single most important decision to initiate therapy * Strongest predictor of subsequent disease progression and survival * Obtain baseline repeated every 3-6 months to re-assess * Viral Load Testing * Obtain plasma viral load at initiation repeated in 2-8 weeks after treatment initiation or alterations in therapy. * Once prescribed stable antiviral regimen, check every 3-4 months

Answer 51

* **CD4 Count \<200** * Pneumocystis carinii pneumonia (PCP) * Aka Pnemocystis jirovecii * Px: Bactrim DS daily or 3 times weekly * **CD4 Count \<100** * Toxoplasmosis * Toxoplasmosis Px: Positive serology àBactrim DS daily * **CD4 Count \<50** * MAI/MAC & CMV (routine px not as clear for CMV) * MAC Px: Azithromycin 1200mg/week * CMV Px: routine px not as clear: Ganciclovir

Answer 52

* Atripla® = **efavirenz** + emtricitabine + tenofovir * \*(1 tab daily: preferably QHS & empty stomach) * Complera® = **rilpivirine** + emtricitabine + tenofovir * \*(1 tab daily: watch if high viral load \>100K viral load) * Stribild = elvitegravir + cobicstat + emtricitabine + tenofovir * \*(1 tab daily: treatment naïve ptns) **“Quad Pill”** * Combivir® = lamivudine + zidovudine (1 tab BID) * Epzicom® = abacavir + lamivudine (1 tab daily) * Trizivir® = abacarvir + lamivudine + zidovudine (1 tab BID) * Truvada® = emtricitabine + tenofovir (1 tab daily)

Answer 53

Odd Ball: **Co bicistat (Tybost)**

Answer 54

CCR5 Antagonist (Entry Inhibitor) ## Footnote **Maraviroc (Selzentry)**

Answer 55

Tenofovir 2 types **_TAF_** and TDF

Answer 56

Protease Inhibitors (PI) * All PIs are associated with **Endocrine type side effects:** * **nHyperlipidemia** * **nFat maldistribution** * **nInsulin Resistance/Diabetes mellitus** * **nOsteonecrosis** * Ritonavir – the booster of all boosters!!! * nAll regimens booster with ritonavir are associated with increased LDL, TG and HDL (esp TG) * nAllow lower dose or less pill burden

Answer 57

**§Efavirenz** * §Teratogenic in nonhuman primates * §Risk of neural tube defects occurs during the first 5-6 weeks of pregnancy, and pregnancy usually is not recognized before 4-6 weeks of pregnancy * §Do pregnancy test before starting EFV (women of childbearing potential) * §Counsel about potential risk to fetus and desirability of avoiding pregnancy while on EFV * §Use alternative ARV agent in women who are trying to conceive or who are not using effective contraception, if feasible

Answer 58

PEP * Raltegravir (Isentress) 400 mg BID * PLUS Truvada Daily * Truvada = tenofovir 300mg & emtricitabine 200mg) Ideally start **within 2 hours of exposure** (best animal data shows w/in 72hrs) Do not delay starting PEP for any reason Continue to take for 28 days (best animal data, not exact science) Medicolegal issues: offer PEP, proper baseline and follow up assessments

Answer 59

* Don’t rely on viral load from finger stick – lots of **false positive** * Who to test? **from age 13 – 75 years old** (atleast once). More often if sexually active or higher risk. * **Juluca**; most common combo drug (2 drugs) * **Acute retroviral syndrome**; primary infection from HIV. **2-4 weeks after exposure**. – **flu, LAD, pharyngitis, rash, myalgiaarthralgia, thrombocytopenia, leukopenia, diarrhea, HA, transaminitis, HSM, thrush, neuropathy, encephalopathy, night sweats**

Answer 60

**HIV in pregnancy**; must be screened at beginning of pregnancy and tested at end of pregnancy * Transmission in; pregnancy, labor and delivery and breastfeeding. * With suppression; risk is \<2% **IRIS**; **immune reconstitution inflammatory syndrome** * Start ART and then elicit previously absent host inflammatory response * Classic; TB, Cryptococcus (wait 4 weeks before starting ART)

Answer 61

* Patient has **untreated HIV**; why she as bone marrow depletion **(pancytopenia)**

Answer 62

Syphilis and HIV

Exam 2 week 2 Flashcards

(88 cards)