Repro- Viruses and antivirals Flashcards
HIV- classification
Retrovirus; diploid ssRNA (+); enveloped
HIV- replication
ssRNA (+) is converted to DNA intermediate by reverse transcriptase and incorporated into the human genome
HIV- key genes (3)
1) GAG => p24, the capsule for RNA strands
2) ENV => makes glycoproteins 160, which is cleaved to gp41 (transmembrane protein) and gp120 (outer glycoprotein)
3) POL => makes reverse transcriptase
HIV- transmission
1) sexual
2) vertical (TORCH)
3) bloodborne
HIV- binding
Initially targets macrophages (CCR5, early) and helper T cells (CXCR4, late)
HIV- latent period; what happens and for how long?
Replication in lymph nodes; lasts up to 10 years
When does HIV become AIDS?
CD4+ T cell count of <200 cells/microliter OR presence of AIDS-defining illness
Cancer directly associated with AIDS
Diffuse large B cell lymphoma
HIV- treatment ‘name’ and usual combination
HAART- highly active antiretroviral therapy; frequently involve 2 NRTIs + another agent
HIV- treatment ‘name’
HAART- highly active antiretroviral therapy
Strategies for treating HIV
1) nucleotide reverse transcriptase inhibitors (NRTIs)
2) Non-nucleotide reverse transcriptase inhibitors (NNRTIs)
3) protease inhibitors
4) Entry inhibitors
5) Fusion inhibitors
6) Integrase inhibitors
Strategies for treating HIV
1) nucleotide reverse transcriptase inhibitors (NRTIs)
2) Non-nucleotide reverse transciptase inhibitors (NNRTIs)
3) protease inhibitors
4) CCR5 inhibition
NRTIs for HIV- mechanism
Nucleotide (or nucleoside) reverse transcriptase inhibitors; incorporated into growing viral DNA strands, but lack hydroxyl group for phosphodiester bond formation
Adverse effects common to all NRTIs
- Mitochondrial toxicity
- Lactic acidosis
NRTIs- common suffix and list
“-dine”;
- Zidovudine
- Lamivudine
- Stavudine
- Didanosine
- Tenofovir
- Abacavir
- Emtricitabine
NRTIs- common suffix and list
“-dine”;
- Zidovudine
- Lamivudine
- Stavudine
- Didanosine
- Tenofovir
Is tenofovir a nucleoside or nucleotide?
Nucleotide (no phosphorylation needed for activation)
HIV drugs used for Hepatitis B
Lamivudine and tenofovir
Zidovudine- AEs
- Myelosuppression (anemia, neutropenia, granulocytopenia)
- Lipodystrophy/central adiposity
Which NRTI causes a rash, and why?
Abacavir causes a type IV hypersensitivity rash in those who carry the HLA-B57:01 allele
Which NRTI causes hyperpigmentation of the palms and soles?
Emtricitabine
Which NRTI causes dose-dependent pancreatitis?
Didanosine
Adverse events of stavudine
Peripheral neuropathy and central adiposity
NNRTIs- suffix and list
“-dine”
NNRTIs- adverse effects
- Hepatic failure: jaundice, flulike symptoms
- Skin rash, which may become Stevens-Johnson syndrome
Efavirenz- adverse effects
- CNS symptoms: dizziness, drowsiness, headache, psychosis
Why do NNRTIs have many drug-drug interactions?
Nevirapine is a moderate inducer of cytochrome P450; efavirenz and delavirdine activate and inhibit the system (and are metabolized by it)
Protease inhibitors: suffix and list
“-navir”
- ritonavir
- atazanavir
- indinavir
Protease inhibitors- MOA
Keeps virion immature by preventing cleavage of long HIV polypeptides (protease encoded by POL gene)
How does HIV build resistance to protease inhibitors?
POL mutations
Protease inhibitors- adverse effects
- Hyperglycemia (insulin resistance, potentially leading to DM)
- Dyslipidemia
- Lipodystrophy
Indinavir- adverse effects
- Nephrolithiasis (within days of starting; maintain hydration)
Which protease inhibitor has the strongest P450-inhibitory effect?
Ritonavir (interacts with Rifampin, which activates P450!!)
What can rifampin be replaced with in patients on protease inhibitors?
Rifabutin
HIV- spread of virions
Virions bud off of infected cells, carrying virion core proteins (p24 and p7) encoded by GAG. ENV codes for envelope proteins crucial for membrane invasion. gp120 must bind to CD4 molecule and a chemokine receptor (CXCR4 or CCR5). gp41 facilitates fusion.
Maraviroc- MOA
Binds CCR5 receptor to block entry (HIV)
Enfuvirtide- MOA
Binds gp41 to inhibit fusion (HIV)
Raltegravir- MOA
Integrase inhibitor disrupts HIV integration into host genome, thus preventing transcription of viral mRNA
What can cause HIV resistance to NRTIs, NNRTIs, protease inhibitors, and integrase inhibitors?
Mutations in Pol (encodes reverse transcriptase, protease, and integrase)
Raltegravir- adverse effects
Rhabdomyolysis (rare)
HPV- classification
Papilloma; dsDNA
HPV- presentation (1-4)
Verruca vulgaris (cutaneous common wart)
HPV- presentation (6 and 11)
- “Low risk” subtypes
- Laryngeal papillomatosis (recurrent respiratory papillomatosis), typically seen in children and may come from vaginal delivery
- STI: Anogenital warts/ condyloma accuminata
HPV- presentation (16, 18, 31, 33)
- “High risk”
- Anogenital cancers, especially squamous cell carcinomas
What type of cells does HPV infect?
Squamous cells
HPV vaccine (Gardasil) coverage
6, 11, 16, and 18
What type of vaccine is Gardasil?
Inactivated subunit vaccine
What is the function of p53 and Rb?
Inhibit transition from G1 to S phase
Function of HPV E6
Promotes proteolysis of p53
Function of HPV E7
Promotes proteolysis of Rb
Detection of cervical cancer? Where, specifically, are cells obtained?
Pap smear at the transformation zone
What is the transformation zone of the cervix?
Squamous epithelium from ectocervix comes in contact with the columnar epithelium of the endocervix
What are koilocytes?
Squamous cells infected with HPV, which have large, dense nuclei (sometimes binucleate)
Name two reasons why HIV+ individuals are at higher risk for cervical carcinoma due to HPV.
1) Immunosuppression
2) HIV is thought to increase expression of E6 and E7
HSV- morphology
Herpesvirus; dsDNA, linear, enveloped
HSV-1- presentation
- Initially as gingivostomatitis
- Cold sores (herpes labialis)
- Keratoconjunctivitis (serpiginous corneal ulcers)
- Temporal lobe encephalitis (hemorrhage and necrosis of inferior and medial temporal lobe, causing bizarre behavior and olfactory hallucination
- Herpetic rash/whitlow
- Erythema multiforme (1-2 weeks into infection)
- HSV esophagitis
HSV-2- presentation
- Herpes genitalis (painful and vesicular)
- Painful inguinal lymphadenopathy
- Herpetic rash/whitlow
- Aseptic meningitis
HSV- diagnosis
- Intranuclear inclusion bodies (Cowdry bodies)
HSV- diagnosis
- Intranuclear inclusion bodies (Cowdry bodies)
- PCR
- Tzank smear (looking for multinucleated giant cells)
HSV- transmission
- Contact
- Sexual
- Vertical (TORCH)
Where does HSV-1 remain during latency?
Trigeminal ganglion
Describe the appearance of herpetic rash
Vesicles on an erythematous base (“dew drops on a rose petal”)
Where does HSV-2 lie dormant?
Sacral ganglia
HSV treatment
Acyclovir or valcyclovir
