Micro: Opportunistic Viral Inf in AIDS

Question 1

What are the three subfamilies of the herpesviridae family?

Answer 1

alpha (HSV-1, HSV-2, VZV) - latency in neurons (sensory ganglia), variable host range, rapid growth in culture
beta (CMV) - latency in secretory glands, lymphoreticular cells, kidneys, other tissues, restricted host range, slow growth in culture
gamma (EBV, KSHV) - latency in lymphoid tissue, difficult to grow in vitro, only family associated w malignancies, inf specific for B or T cells

Question 2

What is the structure of the herpesviridae?

Answer 2

large enveloped, dsDNA
tegument = space b/w envelope and capsid - contains viral proteins and enzymes that initiate replication
Herpes DNA polymerase - promotes viral DNA replication, major target for antiviral drugs

Question 3

How does the herpesviridae replicate?

Answer 3

viral glycoproteins interact w cell surface receptors
nucleocapsid released into cytoplasm through membrane fusion
immediate early genes encode DNA binding protiens
early genes encode transcription factors and enzymes
late genes encode structural protiens
transcribed by cellular DNA dependent RNA polymerase
cells promoting latent transcribe genes w/o genome replication
progression to early and late gene expression associated w lytic replication
replication and assembly in nucleus, virus buds from nuclear membrane and released by exocytosis and cell lysis

Question 4

How is CMV transmitted?

Answer 4

vertical
contact (oral or sexual)
blood transfusion
organ transplant
high antibody seroprevalance in adults

Question 5

What is the pathogenesis of CMV?

Answer 5

establishes persistent and latent inf in mononuclear cells, ductal epithelial cells, and endothelial cells
enlarged cells w intranuclear and intracytoplasmic inclusions (Owls eye)

Question 6

What are the clinical syndromes of CMV in AIDS?

Answer 6

retinitis (majority of cases)
GI dz (colon most common)
neurologic dz (polyradiculopathy most common)
adrenal involvement, pneumonitis

Question 7

What is the presentation of CMV retinitis?

Answer 7

floaters, decreased visual acuity, visual field defects, blurry vision
initially involves one eye
can progress to retinal detachment, blindness
fundoscopic: white fluffy infiltrate and hemorrhagic

Question 8

What is the presentation of CMV esophagitis?

Answer 8

dysphagia and odynophagia
shallow ulcers in distal esophagus
characteristic CMV cells

Question 9

What is the presentation of CMV colitis?

Answer 9

fever, ab pain, diarrhea, maybe dysentery
complications - toxic megacolon, perf
diffuse or patchy colitis, erythema, exudative ulcers, mucosal violaceous hemorrhagic ulcers

Question 10

How is CMV in AIDS diagnosed?

Answer 10

virus detection - PCR, in situ DNA probe hybridization, antigen detection, culture
serology not useful
path on biopsy
empiric (fundoscopic for retinitis)
must find organism in tissue to diagnose end-organ dz

Question 11

What are the treatment strategies for CMV in AIDS?

Answer 11

retinits: 2-3 week induction and lifelong maintenance unless CD4 over 100 for 3-6 mos, if ganciclovir intraocular implant used need systemic also for prophylaxis of other eye
GI dz: 14-21 days or until symptoms gone, maintenance if relapse can be stopped w immune build on HAART
neurologic: longer induction and lifelong maintenance

Question 12

What are the features of ganciclovir as treatment for CMV?

Answer 12

nucleoside analogue phosphorylated by CMV kinase to active form
inhibits viral DNA polymerase by causing DNA chain termination
major toxicity = bone marrow (neutropenia)
poor oral availability
VALGANCICLOVIR has good bioavailability and similar mean time to progression as IV ganciclovir

Question 13

What are the features of foscarnet as therapy for CMV in AIDS?

Answer 13

inhibits viral DNA polymerase by mimicking pyrophosphate portion of nucleotide triphosphates
similar efficacy to ganciclovir but second line
toxicity = renal failure and electrolyte depletion
hydration and careful monitoring required

Question 14

What are the features of cidofovir as therapy for CMV in AIDS?

Answer 14

nucleotide analogue
phosphorylation by virus enzyme not necessary to be active
long half life, induction therapy 1x/wk
toxicities - renal failure, neutropenia
hydration, probenecid and careful monitoring required

Question 15

What are the features of the ganciclovir intraocular implant for treatment of CMV in AIDS?

Answer 15

lasts up to 8 months
locally effective, but no systemic action
generally in conjunction w valganciclovir

Question 16

What are the clinical syndromes caused by HSV?

Answer 16

oral and genital ulcerative dz
pharyngitis, keratitis, whitlow (finger) and gladiatorum (body), encephalitis (not more common in AIDS, CSF shows RBCs), disseminated in neonates

Question 17

What are the features of the clinical syndromes of HSV in pts w AIDS?

Answer 17

disseminated and focal visceral inf rare
can occur at any CD4, worse w lower
relapses more frequent, dz more severe and prolonged
genital HSV increases risk of acquiring HIV
responsive to antivirals, but sometimes resistance to acyclovir - use foscarnet here

Question 18

How is HSV diagnosed?

Answer 18

usually clinically
tzanck smear
PCR or virus isolation/culture from vesicles, tissue, or CSF
serology not useful except epidemiology

Question 19

What is the treatment for HSV?

Answer 19

nucleoside analogs - initial phosphorylation by viral thymidine kinase, cellular kinases then convert to active form - acyclovir, valacyclovir, famciclovir
foscarnet = pyrophosphate analog

Question 20

What is the treatment for VZV?

Answer 20

high dose nucleoside analogue (acyclovir), similar for HIV+ and HIV- except no steroids in +

Question 21

What are the features of VZV in AIDS pts?

Answer 21

pts w CD4 above 200 safe to vaccinate

can occur at any CD4 count

Question 22

What is the epidemiology of EBV?

Answer 22

limited tropism - B cells, some epithelial cells of oropharynx and nasopharynx, expresses CR2/CD21 that binds C3d complement, MHC II are co-receptors
can transform/immortalize B cells
transmitted in saliva - most of the pop sheds intermittently for life

Question 23

When does oral hairy leukoplakia occur w EBV and how is it treated?

Answer 23

CD4 200-500

high dose acyclovir

Question 24

What are the features of primary CNS lymphoma occurring as a result of EBV in AIDS?

Answer 24

CD4 usually under 50, presents w 1 or more mass lesions

dx: head CT (ring enhancing lesions) + biopsy + CSF EBV PCR usually +
tx: HAART, radiation

Question 25

What are the differences b/w non-Hodgkins and Hodgkins in AIDS patients?

Answer 25

non = AIDS defining illness, higher grade and worse prognosis
hodgkins = not AIDS defining illness, higher grade and worse prognosis

Question 26

What is body cavity lymphoma?

Answer 26

in late stages of AIDS
lymphoma cells in pericardium, pleural space, peritoneum, no discrete mass
malignant cells usually + for EBV and KSHV, not T or B cell phenotype but B cell origin

Question 27

What are some clues for distinguishing AIDS pts w primary CNS lymphoma and those w CNS toxo?

Answer 27

toxo usually multiple ring enhancing lesions, lymphoma usually single
lymphoma pts will fail to respond to antibiotics against t. gondii

Question 28

What is the epidemiology of KSHV?

Answer 28

usually MSM spread
virus present in semen, saliva
infects B cells, vascular endothelial cells, spindle cells, others
virus encodes proteins homologous to host proteins that promote growth and prevent apoptosis

Question 29

What are the manifestations of KSHV?

Answer 29

CD4 can be b/w 200-500, visceral involvement usually later
cutaneous: violaceous or brown hyperpigmented vascular nodules, biopsy shows proliferation of spindle cells, formation of new blood vessels
oral cavity/GI KS: GI usually asymx, can perf or bleed, violaceous vascular lesions on mucous membranes, NO biopsy b/c of bleeding risk
pulm: poor prognosis, highly symptomatic, reticulonodular CXR, diffuse interstitial infiltrates, maybe effusions and adenopathy (not in PCP) , dx by bronchoscopic visualization

Question 30

What is the treatment for KS?

Answer 30

HAART for cutaneous only
visceral gets HAART plus radiation/chemo
isolated skin or oral gets intralesional chemo

Question 31

What are the polyoma viruses and when are they a problem?

Answer 31

JC and BK viruses - lytic, chronic, and latent infections
BK: GU inf in transplant pts, not a problem in HIV
JC: PML in advanced AIDS

Question 32

What is the epidemiology of JC PML?

Answer 32

ubiquitous, circulates in lymphocytes and kidney
demyelinating CNS lesions
dx by head CT - nonenhancing white matter lesions, JCV PCR of CSF, brain biopsy - enlarged oligodendroglial cells w inclusions

Question 33

What causes the transformation of the JC virus from a benign inf to PML?

Answer 33

protein large T antigen - binds to and inactivates 2 major growth suppressors, p53 and Rb

Question 34

What are the features of HPV and HIV co-infection?

Answer 34

increased risk of anal neoplasms in HIV+ MSM, risk not decreasing on HAART
conflicting evidence on whether HAART decreases risk of CIN/carcinoma in HIV+ females