Term
Human Immunodeficiency Virus
-etiology |
|
Definition
retrovirus with diploid RNA genome
important components of infectious viral particles:
-ssRNA
-core has viral p24 Gag protein
RNA dependent DNA polymerase - we dont have it, so good selective toxicity
-integrase p11
-protease p32
-surface glycoprotein gp120
-surface glycoprotein gp41
-two strains HIV 1 and 2
-multiple subtypes of HIV1 exist |
|
|
Term
Human Immunodeficiency Virus
-epidemiology |
|
Definition
sole reservoir is humans
-transmission in USA: sexual contact; largest incidence is men with men
-most reported cases are heterosexuals
-concurrent STDS increase risk; men passing to women more likely then women passing to men
transmitted parenterally:
transfusion of blood
IV drug abusers
transmitted mother to child:
high risk
occurs in utero, during birth, or breast feeding
others:
casual contact not a risk factor
organ transplant
occupational exposure (needles) |
|
|
Term
Human Immunodeficiency Virus
-pathogenesis |
|
Definition
A. incubation period 2-4 weeks
B. infection begins with gp120 binding to CD4 cells on T cells and macrophages and chemokine receptors (CXCR4 and CCR5). the binding causes conformational change in gp41 which mediates viral membrane fusion with host cell. viral strains vary in affinity for primary and co-receptors
-gp120 binds CD4
-CD4 is marker for T helper; also found on monocytes, macrophages, dendritic cells
-WITHOUT CO-RECEPTOR infection will not proceed!
-during primary infection as well as asymptomatic stages of infection, predominant HIV strain uses CCR5 co-receptor
-CCR5 is found on memory CD4, activated CD4, macrophages, dendritic cells, monocytes
-as infeciton proceeds, viral phenotype switches to produce HIV subtypes that utilize CXCR4 co receptor (these strains are called X4 or t-trophic HIV)
-CXCR4 co receptor is found on naive CD4 or macrophages |
|
|
Term
Human Immunodeficiency Virus
-pathogenesis
-2 specific subtypes of HIV |
|
Definition
based on cell tropism and syncytium forming ability
1. primary
macrophage-tropic (M-tropic R5 strains)
-infects macrophages/primary T lymphocytes
-non-syncytia forming strains
-predominant HIV strain in primary infection as well as asymptomatic stages that follow
-excellent prognositc indicator of lack of progression to AIDS
2. T lymphocyte-tropic (T-tropic X4 strains)
-infects in PB T lymphocytes and T cell lines
-syncytia forming strains
-T cells do not survive productive HIV infection as macrophages do
-conversion to T tropic strains results in steep decline in CD4 cells and development of AIDS |
|
|
Term
Human Immunodeficiency Virus
-pathogenesis continued |
|
Definition
C. inside cell, ssRNA is converted/transcribed to ssDNA by virus-specified reverse transcriptase and ribonuclease H, then ds DNA
-many mutations occur, hard to treat
D. viral double stranded DNA is integrated into host DNA via integrase p11. latent stage is permanently established
-once infected, person is infected for life, HIV treatment MUST BE LIFE LONG
-until CD4 cell bearing latent HIV genome is activated, there is no expression of HIV components; no virions are produced
--you can suppress active replication, but cannot cure infection
E. activation of HIV and production of virions occurs while double stranded DNA viral genome remains integrated in host genome
-need viral protease p32 to cleave proteins; VIRAL PROTEASE IS TARGET FOR ANTIVIRAL DRUGS
F. HIV causes destruction of CD4 cells via 2 mechanisms: primary effect is depletion of CD4 t cells
-direct infectious cytopathic effect
-indirectly by immunopathogenesis - autoimmune reactions destroy immune system; apoptic cell death
G. acute phase of infection - HIV replicates in T cells of GIT (one half of T cells in human body); most cells gone by third week of infection but depletion is not reflected in peripheral blood CD4 count
-gut is leaky so microbial translocation occurs, which activates immune system; ONE OF THE STRONGEST predictors for progression from HIV infection to AIDs and may be the main cause of CD4 cell depletion
--for 7 years CD8 fight CD4 and HIV then T cells die!
H. after resolving acute HIV, enter clinical latency (no S&S, low viral count in blood, but seropositive); then get diagnosed with AIDS.
during latent period, virus replicates in CD4 lymphocytes in lymph nodes throughout body; eventually virus overwhelms immune system --AIDS |
|
|
Term
Human Immunodeficiency Virus
-manifestations of acute HIV |
|
Definition
fever
lymphdenopathy
pharyngitis
rash - erythematous maculopapular on face, truck, palms, and soles; mucocutaneous ulceration in mouth
myalgias or arthralgia
diarrhea
n/v
headache
hepatosplenomegaly
thrush
neurological symptoms |
|
|
Term
Human Immunodeficiency Virus
-AIDS manifestations |
|
Definition
patients CD4 cell count decreases to less than 200
manifestations due to low CD4 count
-oral esophageal candidiasis
-pneumocystis pneumonia
-cytomegalovirus illness
-mycobacterium avium complex
-cryptococcosis
-toxoplasmosis
-selected tumors
-wasting
-neurological complication |
|
|
Term
Human Immunodeficiency Virus
-neurologic dimensions of HIV infection |
|
Definition
HIV associated dementia - HAD
aka HIV1-associated cognitive/motor complex
aka AIDS dementia complex
-frequent complication of infection with HIV and is defined as slowly progressive demyelinating disease with neuronal loss of CNS
1. incidence of CNS disease - preHAART; common
-even with HAART, cognitive impairment occurs in many people with AIDS and frank dementia occurs in 15% with an annual incidence after onset of AIDS of 5%
-risk factor for progression despite HAART is history of IV drug abuse
-plasma and CSF viral load suppression is a good prognostic indicator |
|
|
Term
Human Immunodeficiency Virus
-pathology of dementia complex |
|
Definition
-HIV directly infects CNS and PNS early in patient's infection
-HIV infection/replication only occurs in monocytes, macrophages, microglia in the CNS
-HIV does not infect neurons or oligodendrocytes
-diffuse or focal myelin pallor of white matter = demyelination
-neuronal loss |
|
|
Term
Human Immunodeficiency Virus
-characteristics of HAD |
|
Definition
infected macrophages (multinucleated giant cells)
astrocytosis
microglial nodules
neuronal loss |
|
|
Term
Human Immunodeficiency Virus
-manifestations of neurological disease due to HIV |
|
Definition
acute and chronic peripheral neuropathies
aseptic meningitis
acute encephalitis
HIV1 associated cognitive/motor complex
painful sensore neuropathy
or
ASYMPTOMATIC NEUROCOGNITIVE impairment - demonstrated by cognitive testing but are asymptomatic in daily life |
|
|
Term
Human Immunodeficiency Virus
-HIV-associated mild Neurocognitive Disorder (MND) |
|
Definition
patient has impairments causing mild disturbance of activities of daily living
ANI and MND are common in era of ART/HAART
-patient has mild difficulties in concentration, attention, and memory may be present
-neurologic examination is remarkable
-lose concentration, every day activities take longer |
|
|
Term
Human Immunodeficiency Virus
-HAD |
|
Definition
diffuse or focal encephalitis; rare due to ART/HAART
if HIV not stopped then:
early changes: MND
-cognitive changes
-motor problems
-behavioral - apathy
Late changes:
HAD
-progression is abrupt - 3-6m until death
-mutism
-incontinence and generalized spasticity
-death
theoretically a person could die of HAD and never be diagnosed with AIDs |
|
|
Term
Human Immunodeficiency Virus
-entire sequence |
|
Definition
without treatment, it is 10 yrs from seroconversion to death due to opportunistic infection and certain tumors (most common) or neurologic complications (less common)
-survival after 1st appearance of AIDS defininig illness, without treatment is 1 yr
ANTIVIRALS AND AB ARE NOT ENOUGH TO CONTROL IT
NEEEDDD IMMUNE SYSTEM!!!!! |
|
|
Term
Human Immunodeficiency Virus
-Diagnosis |
|
Definition
HIV serology - ELISA assay; Western blot
Test for p24 antigen in blood (when donating)
detect viral genome - PCR for plasma HIV RNA to determine viral load for treatment
or
PCF for HIV DNA in wbc
--DONT LOOK FOR AB |
|
|
Term
Human Immunodeficiency Virus
-clinical staging |
|
Definition
HIV
latencyAIDS
M tropic
T tropic |
|
|
Term
Human Immunodeficiency Virus
-treatment
-reverse transcriptin/latency inhibitor |
|
Definition
antiviral /antiHIV drugs - HAART - highly active antiretroviral therapy
two types of drugs target reverse transcriptase and suppress HIV replication from being latently infected; decreased new virus production
1. Nucleoside analogue reverse transcriptase inhibitors (NRTI/RTIs)
ie AZT
-CAUSE CHAIN TERMINATION
competitive inhibitors
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
ie nevirapine, loviridine
-INHIBIT REVERSE TRANSCRIPTASE ENZYME ITSELF, but DO NOT cause chain termination
non competitive inhibitors |
|
|
Term
Human Immunodeficiency Virus
-treatment
-protease inhibitors |
|
Definition
saquinavir, indinavir, amprenavir
prevents viral protease from releasing the individual proteins from molecule so new virions cannot become infectious
--maturation/protein cleavage inhibitors
inhibit viral maturation! |
|
|
Term
Human Immunodeficiency Virus
-treatment
-Fuzeon |
|
Definition
T-20; enfuvirtide
inhibits viral fusion into host cell
-fusion inhibitor |
|
|
Term
Human Immunodeficiency Virus
-treatment
-selzentry |
|
Definition
maraviroc
-inhibitor of HIV1 co-receptor CCR5
-attachment/binding inhibitor |
|
|
Term
Human Immunodeficiency Virus
-treatment
-raltegravir |
|
Definition
also sold as isentress
inhibitor of HIV1 integrase
-integrase inhibitor |
|
|
Term
Human Immunodeficiency Virus
-treatment
-monotherapy |
|
Definition
NOT EFFICACIOUS LONG TERM due to high mutation rate of virus
one drug is never enough! |
|
|
Term
Human Immunodeficiency Virus
-treatment
-HAART |
|
Definition
2RTI plus either NNRTI or protease inhibitor
-does not stop all new infections; not 100% effective
-not a cure! intact virus and integrated, latent viral genome are unaffected
-even if no viral RNA level in blood, patient still infectious via sexual contact
-drug resistant HIV occurs even with HAART and is major problem in patients due to high mutation rate
SERIOUS PROBLEM!
-key questions: when should it start, what regimen should be used, when should therapy change, what should it change to?
treat ppl will less than 200 CD4
treat ppl with symptoms
treat people with CD4 between 200 and 350
-intermittent therapy depending on CD4 counts is not a good option; should be CONTINUOUS
bc drug resistance always a problem, latent cells still remain
DELAY TREATMENT BECAUSE SO MANY PROBLEMS; easy to reach toxicity
use of HAART restricted to:
HIV associated cognitive motor complex
cryptococal meningitis
CNS toxoplasmosis
primary CNS lymphoma
MANY ADVERSE EFFECTS OF HAART |
|
|
Term
Human Immunodeficiency Virus
-prevention |
|
Definition
education
clean needles
barrier techniques |
|
|
Term
Epstein Barr Virus
synonyms / etiology |
|
Definition
heterophile-positive infectious mononucleosis (glandular fever)
aka kissing disease
EBV is part of herpesvirus group; HHV4 |
|
|
Term
Epstein Barr Virus
-epidemiology |
|
Definition
saliva
worldwide; lifelong
subclinical in early childhood
poor sanitation
like polio, infectious mononucleosis (mono) is diagnosis of industrialized countries
when young adults are exposed to EBV, many of them manifest with IM |
|
|
Term
Epstein Barr Virus
-pathogenesis |
|
Definition
virus produced in epithelial cells of oropharynx with release of virus in saliva for weeks to months
-infection of B lymphocytes occurs early in infection; virus remains latent in these cells lifelong
-latently infected B lymphocytes proliferate/undergo hyperplasia
-EBV is type 1 t-ind antigen
polyclonal B cell response results in hypergammaglobulinemia
-B lymphocytes spread to blood where they are destroyed by EBV cells |
|
|
Term
Epstein Barr Virus
-manifestations |
|
Definition
long incubation; 2-3 wks
prodrome 3-5 days; flu like symptoms; fever headache, general malaise, lethargy
presentation:
lymphadenopathy (back of neck, armpits)
pharyngitis
fever up to 3 wk
splenomegaly
hepatomegaly
fatigue
disease may linger for up to 1 yr |
|
|
Term
Epstein Barr Virus
-EBV assoicated disease |
|
Definition
1. chronic active EBV aka chronic mononucleosis
-rare
2. lymphomas:
nasopharyngeal carcinoma
burkitts lymphoma
non-hodgkin's lymphoma
hodgkin's disease
3. hairy oral leukoplakia - lesions on tongue; treat with acyclovir
4. other: MS; predicted by rising igG titer against EBNA and VCA
-can occur within 4-5 yrs |
|
|
Term
Epstein Barr Virus
-diagnosis |
|
Definition
-present with manifestations
-atypical lymphocytosis (downey cells)
-positive heterophile AB test
-EBV specific antibodies (igM or IgG; not protective |
|
|
Term
Epstein Barr Virus
-differential diagnosis |
|
Definition
CMV!!!!! (heterophile negative IM; if its this, then no treatment; no acyclovir or ampicillin
-viral hepatitis
-acute toxoplasmosis
-rubella
-HIV primary infection
-strep throat
-viral pharyngitis |
|
|
Term
Epstein Barr Virus
-treatment |
|
Definition
| largely supportive, patient will recover without specific therapy |
|
|
Term
Cytomegalovirus (CMV)
-etiology |
|
Definition
| CMV is herpesvirus group; called HHV5 |
|
|
Term
Cytomegalovirus (CMV)
-epidemiology |
|
Definition
MOST are asymptomatic infections
leading cause by far of infection and morbidity in neonate
one of most frequent disseminated opportunisitc infection seen with AIDS
primary and recurrent infection
-with recurrent, it is either reinfection or reactivation of infection |
|
|
Term
Cytomegalovirus (CMV)
-transmission |
|
Definition
close contact with urine, salive, secretions
-blood transfusions
-vertical transmission due to mom with primary or recurrent infection
-in utero, during birth, breast feeding
-primary infection in mom is big concern bc immune pregnant woman results in asymptomatic congenital infection in infant
--MOST COMMON CAUSE OF CONGENITAL INFECTION
organ transplant recipient
-most develop due to immunosuppression
sources: environmental, transplanted organs (both are primary infection)
transplant pateitn (reactivation infection |
|
|
Term
Cytomegalovirus (CMV)
-pathogenesis |
|
Definition
CMV infects:
many cell types
site of latency is not identified - dont knw where it is reactivated
immunosuppression reactivates latent CMV
both humoral and cellular immune responses are important in CMV infections |
|
|
Term
Cytomegalovirus (CMV)
-clinical features |
|
Definition
in neonates with fulminant congenital cytomegalic inclusion disease CID:
infection of liver, lungs, eye-retina, brain
if asymptomatic at birth then develop into progressive, late onset, bilateral sensorineural hearing loss
-vision loss, neurological deficits, behavioral changes
CMV symptomatic infection acquired in infancy:
first 3m, lymphadenitis, pneumonitis, hepatosplenomegaly, rash
CMV induced mononucleosis
-in young adults
symptomatically indistinguishable from EBV infectious mono
complication:
hepatitis, meningoencephalitis, mycorditis, guillian barre |
|
|
Term
Cytomegalovirus (CMV)
-diseases associated with infection |
|
Definition
pneumonia
retinitis- causes blindness in AIDS pt
encephalitis
gastroenteritis |
|
|
Term
Cytomegalovirus (CMV)
-laboratory diagnosis |
|
Definition
suspect CMN mono in any case of infectious mono where heterophile agglutin test is negative and patient has fever of unknown origin
observe "owls eye' appearance in tissues or urine (congenital)
atypical lymphocytosis (downey cells) like EBV-IM
use TORCH for igM in chord blood |
|
|
Term
Cytomegalovirus (CMV)
-treatment |
|
Definition
for IM: largely supportive, patients recover without specific therapy
for reactivation:
ganciclovir, foscarnet, cidofovir (acycylovir resistant)
antisense product formivirsen for treatment of CMV retinitis that dont respond to above. inject into eyeball. |
|
|
Term
Cytomegalovirus (CMV)
-prevention |
|
Definition
| vaccine or passive immune prophylaxis |
|
|
Term
Cytomegalovirus (CMV)
-vaccine |
|
Definition
orphan drug status
prevents CMV viremia, CMV disease, associated complications |
|
|
Term
Cytomegalovirus (CMV)
-passive immunity |
|
Definition
| use CMVIG if kidney transplant patient receives seropositive kidney |
|
|
