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Microbiology 8


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HIV -- tat protein
encourages new virus production

binds to a host cell cyclin dependent kinase and allows host cell RNA polymerase to make a full length HIV RNA without aborting prematurely
HIV -- rev protein
binds certain HIV RNAs to move them out of the nucleus so they can be translated into peptides & polypeptides or be packaged into new virions
HIV protease
proteolytic cleavages of HIV (gag, pro, and pol) precursor polypeptides are carried out by viral enzyme protease within the immature HIV particle just after it has budded from the cell
Nuceloside Reverse Transcriptase Inhibitors (NRTIs)
- mechanism of action
- are analogs of the dNTPs
- are sequentially triphosphorylated by HOST CELL enzymes (except tenofovir which already has one phosphate group making it a nucleotide reverse transcriptase inhibitor)
- in active triphosphorylated form they compete with host cell supplied dNTPs for binding in the active site of HIV RT (have higher affinity for viral RT than host polymerases)
- are chain terminators
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- mechanism of resistance
- result of mutations in or near the RT active site such that the drug is either removed from the DNA chain or excluded from competing with the natural dNTPs.
ACT, zidovudine (Retrovir)
- drug type?
- side effects

anemia, neutropenia
D4T, stavudine (Zerit)
- drug type?
- side effects

peripheral neuropathy, peripheral lipoatrophy
DDI, didanosine (Videx EC)
- drug type?
- side effects

peripheral neuropathy, pancreatitis
Abacavir (Ziagen)
- drug type?
- side effects
NRTI (Note: this is an exception to my rule of -avir = PI)

hypersensitivity Synd. -- Fever, rash, abdominal pain +/- nausea / vomiting
Non-Nuceloside Reverse Transcriptase Inhibitors (NNRTIs)
- mechanism of action
- highly specific for HIV-1
- bind to a "hydrophobic pocket" near but not in the RT active site inducing a conformation change that results in a much less efficient RT polymerase
efavirenz (Sustiva)
- drug type
- side effects
- contraindications

CNS side effects in 50%

don't use in pregnancy, teratogenic
neveripine (Viramune)
- drug type
- side effects

rash, hepatitis -- especially with CD4 > 250
Protease Inhibitors (PIs)
- mechanism of action
- structures typically mimic the aromatic peptide bonds that HIV Protease cleaves

- inhibition of cleavage of gag and gag-pol precursors results in failure of newly budded virion to mature
Protease Inhibitors (PIs)
- mechanism of resistance
- typically 4-8 mutations required for high level resistance
- mutations in HIV protease gene probably prevent PIs from entering or binding active site
- drug type
- side effects

lipodystrophy syndrome
lipodystrophy syndrome
seen with HIV protease inhibitors

a constellation of central / thoracic fat pad accumulation, peripheral lipoatrop, elevated LDL, triglycerides, and glucose intolerance
ritonavir (norvir)
- drug type
- side effects

Lipodystrophy synd
Indinavir (Crixavan)
- drug type
- side effects

kidney stones

Lipodystrophy synd
Nelfinavir (Viracept)
- drug type
- side effects

diarrhea common

Lipodystrophy synd
fosAmprenavir (Kaletra)
- drug type
- side effects

Lipodystrophy synd
3TC, FTC, Tenofovir all active vs. what?
all active vs. both HIV and Hep B
what is the best studied anti-HIV combo used in patients who were naive to previous antiretroviral therapy
AZT + 3TC + Crixavan
T20 (Fuzeon)
inhibitor of HIV entry

recently approved but high cost, limited availability, and need to give subcutaneously limit its use
Nucleoside & Nucleotide analogs
- used against which virus type?
- mechanism of action
used against Herpesviruses

Nucleoside & Nucleoside analogs

- dNTP analogs that compete for the active site in herpesviral polymerase
- 1st phosphorylation is performed by viral kinases (except cidofovir)
Acyclovir -- spectrum of activity
HSV 1& 2 (low dose) and VZV, EBV, and Herpes B viruses (high dose)
ValACV & PenCV -- spectrum of activity
high intracellular levels improve achievable activity vs. VZV and EBV slighly and for ValACV add marginal activity vs. CMV
Ganciclovir, Valganciclovir, and Cidofovir -- spectrum of activity
good activity vs CMV, HHV6, and possibly HHV8, as well as activity vs HSV, VZV, and EBV
Cidofovir -- spectrum of activity
active against adenoviruses papilloma viruses, pox viruses
Ganciclovir (Cytovene)
- side effects
anemia, neutropenia
Valganciclovir (Valcyte)
- side effects
anemia, neutropenia
Pyrophosphate analogs
- e.g.
- resistance
- spectrum
e.g. Foscarnet

- a pyrophosphate analog -- binds pyrophosphate site on polymerase blocking it

resistance: viral DNA pol mutation

active vs. all human herpesviruses, also some activity vs HIV
Hyperimmune globulins
- mechanism
- pooled serum immune globulins (Ig) from patients with high titers to the virus in question
- has typical properties of mostly IgG immunoglobulin -- neutralizing activity, opsonizing, ADCC
used to prevent and treat CMV infections in transplant recipients and prevent perinatal transmission
major use is in very young infants or immunocompromised children significantly exposed to VZV
Interferon-alpha and Pegylated interferon-2a
- e.g.
e.g. Interferon-alpha (Roferon-A, Intron-A) and Pegylated interferon-2a (Pegasyn)

- recombinant versions of a natural human glycoprotein cytokine, interferon
- induces an "antiviral state" within cells (inhibits viral RNA transcription, degrades viral mRNAs, and interferes with translation by multiple mechnisms
- induces cytotoxic T cell and NK activity and upregulates MHC proteins
are nucleoside & nucleotide analogs active vs. hep C?
No, because Hep C is an RNA virus
is Ribavarin active vs. Hep B?
- guanosine analog that after triphosphorylation by host kinases interferes with several processes including capping of mRNA (influenza) and in some viruses it may interfere with viral RNA polymerase or RT activity
- for Hep C, inhibition of host IMPDH may play a key role
- side effects
anemia, contraindicated in pregnancy
M2 Ion channel inhibitors
M2 Ion channel Inhibitors

- After influenza virus attaches to a cell via HA binding to sialic acid residues, it is internalized into an endosome which becomes acidified
- Influenza M2 proteins form a channel to pump H+ ions into the virion from the surrounding acidic host cell endosome, allowing coiling in HA that results in fusion of viral and endosome membranes and release of viral ribonucleoproteins into cytoplasm (uncoating)
- Amantidine and Rimantidine block influenza A M2 ion channel activity
Amantadine and Rimatidine
- drug type
- active against what specifically
M2 Ion Channel Inhibitors

active only against Influenza A
Neuraminadase Inhibitors
active against Flu A&B

- neuraminidase (NA) cleaves the terminal sialic residues from the cell surface viral receptors, enabling release of new virus particles from infected cells
- inhibition of NA results in aggregation of viral particles within the cell
Zanamivir & Oseltamivir
- drug type?
Neuraminadase Inhibitors
what are the eight human herpesviruses?
(1) HSV-1
(2) HSV-2
(3) VZV
(4) EBV
(5) HCMV
(6-8) HHV-6, -7, -8
- broad host range, rapid reproductive cycle, latent infection of sensory ganglia

e.g. HSV-1, HSV-2, VZV
- relatively restricted host-range, slow reproductive cycle, cytomegalic, latent infection of secretory glands, lymporeticular cells, kidneys, lymphoid tissue

- restricted host range, lymphotropic, latent infection of B-lymphocytes

where do herpesviruses replicate?
in the nucleus
treatment for HSV
acyclovir -- chain terminator of viral DNA synth

reduces severity and during of clinical symptoms but does not prevent establishment of latency
Varicella Zoster
- chicken pox
- one serotype and narrow host range
- spread from individuals with primary or recurrent infection via respiratory droplets
- latency in dorsal root ganglia
HIV gag sequences
code for the major structural proteins that are antigenic

Nucleocapsid (NC), capsid (CA, aka p24), and matrix (MA) proteins
HIV pol sequences
encodes the vital protease, integrase, and reverse transcriptase enzymes
HIV env sequences
codes for the ENVelope proteins that, once glycosylated, form the glycoprotein spikes gp120 and gp41
list four main changes in the epidemiology of HIV transmission
DEC perinatal transmission

INC heterosexual transmission

INC gay male transmission

DEC IV drug use transmission
Since 1995 has there been a significant change in the incidence of new HIV infections?
what is considered a low T cell count in HIV?
T cell < 100
what is considered a normal T cell count?
T cell > 600
what is the clinical use of HIV viral load?
correlates with disease progression and treatment efficacy
T/F a HIV viral load of 10,000 copies / mL indicates low risk of progression
T/F a HIV viral load of 75,000 copies / mL indicates low risk of progression

viral load > 50,000 copies / mL indicates greater risk of disease progression
T/F Undetectable viral load means HIV has been eradicated
F, just means that therapy is effective
T/F Undetectable viral load means absence of infectivity
what is the main opportunistic infection to remember if CD4 is 200-500
pneumococcal pneumonia
what is the main opportunistic infection to remember in HIV if CD 4 < 200
pneumocystis jiroveci pneumonia (dry cough / fever)
List the prophylaxes for OI's given to HIV+ patients, depending on CD4 count
Any CD4
- pneumococcal, influenza, HepB vaccines
- INH for latent TB infections (+ TB skin tests)

CD4 < 200

pneumocystis prophylaxis

CD4 < 100

toxoplasma prophylaxis

CD4 < 50

MAC (myco. avium complex) prophylaxis
- buffalo hump
one of the problems with Highly Active Antiretrovial Therapy (HAART) -- can get fat redistribution
name 5 indications for when to use HAART treatment
(1) symptomatic HIV infection

(2) CD4 < 200

(3) Viral load > 50,000 (controversial)

(4) primary HIV infection (or recent acquisition)

(5) pregnancy
what is the main reason for HAART failure?
which particular Protease Inhibitor is actually good at inhibiting the metabolism of other Protease Inhibitors (thus inc their levels)?
how to remember PI names?
all end in -avir
how to remember Nucleoside & Nucleotide analog names (Anti-herpesviral drugs)?
all end in -ovir
Specific mech of Ribavirin against HepC?
inhibition of host IMPDH may play a key role
what is one very important (OTE) point about the metabolism / side effects of Ribavirin?
concentrated in RBCs / can lead to anemia
How to remember the M2 ion channel inhibitor names?
end in -tadine
how to remember the Neuroaminidase inhibitor names?
end in -ivir
both the ion channel inhibitors and the neuranimidase inhibitors reduce the duration of flu symptoms by 1 - 2.5 days IF . . .
if started by 2 days of symptom onset
Why drug should be avoid in children with influenza or VZV infection due to association with Reyes syndrome?
which virus accounts for 15% of the cases of mononucleosis?
what is the only human herpesvirus that can be transmitted transplacentally to the developing fetus?
CMV --> this can result in serious birth defects!
what is the causative agent of roseola and what are the symptoms?
HHV-6 is the causative agent of roseola (high fever and severe rash).
heterophile antibody
- an IgM that recognizes the Paul-Bunnell antigen on sheep and bovine erythrocytes

- serves as a marker for EBV mononucleosis and can generally be detected by the end of the first week of illness
what is the one human herpesvirus that is relatively uncommon?
proto-oncogene -- normal host genes which when mutated or altered in expression can lead to tumor formation
oncogene -- gene thought to be capable of producing cancer
do chronic transforming retroviruses encode oncogenes?
herpesviridae envelope
Herpesviridae (i.e., HSV1, HSV2, CMV, EBV,HZV) have an envelope which is a lipid bilayer which it gets from the cell nucleus. These viruses are the only DNA viruses (that infect humans) that have a lipid bilayer.
hepadnaviridae envelope
Hepadnaviridae are DNA viruses that have an "envelope" also. But, it is not a lipid bilayer. Their lipid comes in the form of lipoprotein (and looks like high density lipoprotein). This lipoprotein is a major component of the surface antigen of these viruses. For the human virus in this family (i.e., the hepatitis B virus) this lipoprotein-like material is known as hepatitis B surface antigen (HBsAg).
poxviridae envelope
Poxviridae are DNA viruses that also have an "envelope". Again, this lipid material is not a lipid bilayer. In fact, these viruses synthesize their own lipid and do so within the cell that they infect. Their lipi is complexed with protein. Lipids of Poxviridae are distinctive from those of the cell that they infect (as can be determined through various lipid chromatography methods).
most important cause of respiratory disease in infancy (less than 6 months old) particularly of bronchiolitis and pneumonia
respiratory syncytial virus (RSV)
newcastle disease conjunctivitis
primarily a disease of fowl

occupational hazard of human, inflammation of the conjunctiva
- what type of nucleic acid
name four poxviruses that primarily infect humans
(1) smallpox (variola major)

(2) allastrim (variola minor)

(3) vaccinia

(4) molluscum contagiosum
- general info
large, enveloped, RNA viruses with helical nucleocapsid and single stranded RNA (linear, non-segmented); envelope has large club-shaped spikes
- what conditions is it responsible for?
10-15% of upper respiratory tract infections and pneumonias ("colds") in humans, primarily in adults

also associated with enteritis in children

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