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HIV/AIDS
Nester 5th ed
Chapter 29
The Origin of HIV

HIV most likely came from monkeys
• 1995 a virus was discovered that was
genetically half way between HIV and SIV
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Evaluation of the rate of genetic change of
HIV shows that common ancestor arose
between 1915 & 1941 - most likely 1931.
Beginnings - continued
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HIV-1 came from chimpanzees.
HIV-1 group M is worldwide.
• It has a single origin - one man or one chimp.
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HIV-1 in the US evolved between 1960 and
1971 - most likely 1967.
Alerts us to dangers of cross-species
transmission
Beginnings - continued
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HIV-2 came from sooty mangabeys.
Similar structure to HIV-1
Antigenically distinct
> 55% of the genome differs from HIV-1
Found in West Africa and India
Transmission less efficient
Disease progression is slower.
Beginnings
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1981 in San Francisco
5 previously healthy homosexual men had
unusual health problems
• unusual opportunistic infections
• certain tumors
• immunodeficiency
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This clustering of cases of a new disease led
to an amazing public health story
HIV/AIDS Epidemic two decades after the onset
The Virus
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Retroviridae
• Lentiviruses
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SS RNA
Ten HIV subtypes (a-j) in group M
Found in many diverse species - e.g. horse
Immunosuppressive disease
Neurological disease
Tumors
HIV Structure
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Figure 29.3a
Surface glycoprotein (SU) - gp120
Transmembrane glycoprotein (TM) - gp41
Matrix protein (MA) - p17
Capsid protein (CA) - p24
HIV Structure
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HLA from host cell membrane
Lipid envelope - host plasma membrane
Two strands of ss RNA
Reverse transcriptase (RT)
Protease (PR)
Integrase (IN)
HIV Genome
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Figure 29.3b
LTRs -host cells recognize long terminal
repeats
gag gene - yields MA, CA, NC
pol gene - yields PR, RT, IN
env gene - yields gp120 and gp41
Group antigen
polymerase
HIV Genome
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Figure 29.3c
gag & pol transcript is cleaved by a viral
protease
• gag and pol split into 3 enzymes - PR, RT, IN
• gag is split into p24, p17 and other proteins
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env- translated from a spliced mRNA
• precursor processed by host protease
HIV Genome
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Accessory genes - translated from spliced
mRNA’s
• Interact in different ways with host cell
substances
• Varies with cell type infected
• HIV with defective nef might be a vaccine
• tat might be a factor in Kaposi’s sarcoma
• Vpr might be used to stop growth of tumor cells
The Term AIDS
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Acquired immunodeficiency syndrome
Term used first in 1982 by the CDC
Used to define diseases that predict that
someone would have low resistance to
disease
More than one immunodeficiency disease
HIV disease caused by HIV is just one
Symptoms of HIV Infection
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Incubation period is 6 days to 6 weeks
The acute disease lasts about 6 weeks
Most cases are asymptomatic
Some cases are “flu-like and not severe
• Often these mild symptoms are ignored
Symptoms of HIV Infection
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Some cases have
• Fever, headache, sore throat, muscle aches,
enlarged lymph nodes, and a generalized rash
• CNS disturbances like moodiness, confusion,
seizures, paralysis and encephalitis
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Asymptomatic period follows
• Usually lasts years
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Transmission can occur all during this time
Symptoms of HIV Infection
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PGL - persistent (or chronic) glandular
lymphadenopathy
• Can lasts from acute disease through AIDS
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LAV - lymphadenopathy syndrome
• Occurs at the end of the asymptomatic period
Symptoms of HIV Infection
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ARC - AIDS related complex
• Characterized by less severe opportunistic
infections
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AIDS - severe immunodeficiency
Table 29.1- AIDS defining conditions
Pathogenesis
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Figure 29.4
• Intestinal epithelium
• Brain cells
• Dendritic and other APC’s (antigen presenting
cells)
• CD4 (T-helper) lymphocytes
• CD8 (T-cytotoxic) lymphocytes
• CD4+ macrophages
Impairment of chemotaxis,
phagocytosis and antigen
presentation
Cytokines of TH regulate
cytotoxic action of Tc
cells, immunoglobulin
production
HIV cellular targets
Pathogenesis
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Cells with CD4+ markers
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Helper T-lymphocytes
Monocytes
Tissue macrophages
Dendritic cells of lymph nodes
B-lymphocytes (especially if infected with
EBV)
Pathogenesis
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Cells without CD4+ markers
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Epithelial cells of intestine and vagina
Neurons
Astrocytes
Oligodendroglia
Microglia
Bone marrow stem cells
Capillary endothelial cells
Pathogenesis
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Virus replication
• Attachment - Figure 29.5
Receptor on cell
• Ligand on virus
• Co-receptors - cytokine receptors
– CCR5 on macrophages
– CXCR-4 on T-lymphocytes
• Penetration
• Uncoating
Attachment and entry of HIV into a host
Steps in HIV replication
Pathogenesis
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Virus replication - Figure 29.6
• RT makes a ds DNA from RNA in cytoplasm
• Circularizes and integrates randomly - provirus
• Spliced mRNA segments - from tat, rev, and
nef genes
• New genome RNA is made
• Synthesis of structural components
• Assembly and release by budding
Pathogenesis
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HIV variability
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High rate of error of the RT
Two genome pieces - RT can transcribe both
Some regions of genes are conserved
Some regions are variable
Some variants infect some cells better
Some variants replicate faster or slower
Surface glycoprotein gp120
Pathogenesis
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Destruction of cells by HIV
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Virally induces cell lysis
Attack by HIV specific CD8+ cells
Natural killer cells
ADCC
Autoimmunity
Fusion of infected and uninfected cells
Apoptosis
Pathogenesis
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Clinical features
• See graph - in notes and book Figure29.8
• Immune system slowly fails
• CD4+ cell counts used for prognosis
• Normal 1000/microliter
• < 200/microliter - symptoms of AIDS
Natural history of HIV
Pathogenesis
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Atypical case
• People with virus levels that don’t fall
• 10% cases
• AIDS in a few years
• People with a good immune response
• 5% to 10%
• Progress more slowly
• Some will still be free of AIDS 20 years
later
Epidemiology - Global
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>33,400,000 cases worldwide
Most cases in developing countries
Africa - 67%
Asia - 22%
South America and Caribbean - 5%
North America - 2.7%
Europe - 1.5%
Epidemiology - Global
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Global death toll 16.3 million
#1 killer in Africa even passing malaria
By the end of 2000, 10.4 million children
under 15 will be orphans.
India is fast becoming the single country
with the most HIV cases.
A new case occurs every 6 seconds
Epidemiology - U.S.
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Number of cases - 890,000
Number of deaths - 420,000
30,000 new cases each year
Epidemiology - U.S.
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Women - increase is alarming - Figure 29.9
Women who have sex with bisexual men or
IV drug abusers
> 80,000 HIV (+) women may leave
150,000 children
In the United States rising percentage of AIDS cases in women
Epidemiology - U.S.
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Women – Cont.
1/10 HIV (+) women will miscarry
Live births 15-40% get AIDS unless mother
is treated
3% of babies may clear infection w/out
treatment
Epidemiology – U.S.
Age at Diagnosis
Number of Cases
30000
25000
20000
15000
10000
5000
0
0
25
30
35
40
45
50
70
Epidemiology - U.S.
State or Territory
Rate per 100,000
Washington, D.C.
182
Puerto Rico
71
New York
68
Florida
58
New Jersey
56
Epidemiology - U.S.
State or Territory
Rate per 100,000
Wyoming
3.9
Montana
2.9
South Dakota
2.6
North Dakota
0.8
Epidemiology - U.S.
Type of Transmission
Injecting drug user
Heterosexual transmission
Sex with injecting drug user
Sex with men of other risk
Other/undetermined
Transfusion recipient
%
45
39
21
18
12
4
Transmission
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Blood
• Drug addicts who share needles
• Hemophiliacs who got Factor VIII pre-1985
• Post surgery patients pre-1985
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Sexual
• Homosexual and bisexual men
• Heterosexual
• HIV (+) mother (or risky behavior) to child
Transmission
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Body fluids where HIV is found
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Blood
Semen
Vaginal and cervical secretions
Urine
Feces
Mother’s milk
Saliva*, tears, sweat
Transmission
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HIV is not spread by:
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Touch or hugs
Swimming in a chlorinated pool
Food
Sharing dishwasher, washing machine
Giving blood or doing blood tests
Bathrooms*
Mosquitoes
Transmission
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HIV’s environmental and chemical
inactivation
• HIV persists for a week in plasma removed
from a patient
• HIV is hard to inactivate in dried pus or blood
• HIV is susceptible to high level disinfectants
• HIV is susceptible to >= 560 C (1320 F)
• For 30 minutes
Prevention
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Office disinfection procedures
• 10% bleach
• Really the best but has draw backs
• Should be used on any surface that won’t be harmed
by repeated use of bleach.
• Should be made up before each use.
• Works better if warm water is used to make up the
solution
Prevention
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Office disinfection procedures
• High level disinfectants destroy all viruses
• Can be used on almost any surface
• Fumes may be less bothersome than bleach
• Need to read each container for proper mixing
instructions
• Need to check toxicity
Prevention - Table 29.3
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Abstinence from any risky behavior
Reduce sex partners - know partners well
Use latex barriers and water soluble
lubricants
Newer polyvinyl barriers are OK
Treat HIV (+) persons with anti-viral drugs
Prevention - Table 29.3
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Expand all forms of education to all age
groups
• Persons older than 50 were not being informed
• Persons >= 50 account for 15% of new cases in NY
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Don’t expose vagina, penis, anus or mouth
to semen, blood, menstrual blood, vaginal
secretions, urine or feces
Prevention
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Perinatal transmission
• Diagnosis and treatment of STD’s
• Prenatal care and anti-viral therapy
• Non-invasive pre and intrapartum care to
reduce blood exposures
• Mild anti-septic wash of vagina and newborn
• minimize delivery time after membrane rupture
• C-section if necessary
Prevention
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Vaccines
• Could be used in two ways
• To immunize uninfected people
• To boost immunity of HIV (+) individuals before
their immune system is destroyed
• Best hope of understanding natural clearance
• African prostitutes with no disease
• Newborns that clear the virus
Prevention
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Vaccines must:
• Induce IgA as well as IgG but no enhancing
antibodies.
• Stimulate cell mediated.
• Get around HIV antigenic variability - use
antigens that are stable.
• Be safe - no reversion, no induction of tumors,
no autoimmune disease, etc.
Prevention
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Vaccines in phase I
• Component vaccines
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Purified gp120 and gp160
Synthetic surface proteins
Synthetic lipopeptide
Naked DNA containing env genes
Prevention
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Vaccines in phase I
• Viral vaccines
• Vaccinia + gag and env grown in cell culture
– virus-like particles form with surface antigens of HIV
• Canary pox virus with HIV env genes for surface
antigen
• Vaccinia + HIV env genes for surface antigens
Prevention
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Vaccines in Phase III
• Only gp120 vaccines
• Thailand - gp120 from two HIV strains
• North America - gp120 from two HIV strains
• Two subtype B strains
Tumors
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Kaposi’s sarcoma
Lymphomas
Carcinomas of anal or cervical epithelium
Kaposi’s Sarcoma
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Malignant tumor of the endothelium of
blood and lymphatic vessels
• Rare tumor in elderly men of Mediterranean or
Eastern European origin
• In all ages of certain parts of tropical Africa
• Tumor regresses if a women becomes pregnant
• HHV-8 found in Kaposi’s tumors - ?????
Kaposi’s sarcoma
Lymphomas
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Usually B-cell tumors
Can be T-cell tumors
In 5-10 % of HIV patients
EBV may be a cofactor
• Burkitt’s lymphoma - 1000X more than in
general public
Hairy leukoplakia activation of latent Epstein-Barr
virus infection
Lymphomas of the Brain
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Usually rare
• 25% of AIDS patients have them
• EBV found in these tumors
Cervical and Anal Carcinoma
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Associated with HPV types 16 and 18
HIV lowers immunity to these viruses are
not kept in check
A woman should be checked regularly for
cervical cancer if she is HIV(+)
Women and homosexual men should be
checked regularly for anal cancer
Opportunistic Infections
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Pneumocystosis
Toxoplasmosis
Cytomegalovirus disease
Mycobacterial diseases
Pneumocystis carinii
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Tiny fungus that causes severe lung disease
Slow onset, shortness of breath, rapid
breathing, dusky appearance
1-3 micrometer spores - inhaled, attach to
alveolar sac walls, alveoli fill with fluid and
mononuclear cells, alveolar wall thicken
and scar, oxygen exchange is reduced
Pentamidine
Toxoplasma gondii
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Protozoan that causes toxoplasmosis
10% of healthy, exposed adults get sick
Disease is like “infectious mono”
Congenital disease is very severe
• Disease of mother involves fetus - 50%
• Most cases occur in last trimester
• Retinitis, mental retardation, epilepsy
Cytomegalovirus
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HHV-5 is latent in glands and kidneys
Cytomegalic inclusion disease
Congenital cytomegalo virus disease
• hearing loss, mental retardation
• congenital CMV in 1% of live births
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Probably an STD
Severe disease in the immunocompromised
Mycobacterial Infections
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Mycobacterium tuberculosis
Mycobacterium avium complex (MAC)
• avium and intracellulare
• species that do not usually cause severe disease
in people
Mycobacterial Infections
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Elderly with chronic lung disease
• chronic cough, productive sputum
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Children
• chronically enlarged lymph nodes
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Immunocompromised
• cough, sputum, sweats, weight loss, diarrhea
Factors in Long Term Survival
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Strong CD8+ anti-viral response
Relatively non-virulent virus strain
Low amount of virus in plasma and PBMC
No immunological decline
Non-progressors represent 5% of the total
HIV infected population
Structure & function of lymph node is good
Factors in Faster Progression of
AIDS
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MHC (HLA) type
Age - young, old
Viruses
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EBV, CMV, HSV-1, HHV-6
Adenoviruses
HBV
HTLV 1 & 2
Factors in Progression of HIV
Infection
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Genetic factors like CCR5 and CXCR4
Chemokine receptor gene CCR5
• Homozygous wild type – normal progression
• Heterozygous wild type/32bp deletion - delayed
progression
• Homozygous 32bp deletion - delayed
progression
• Deletion is found in Europeans - not sure why
Factors in Faster Progression of
AIDS
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Clinical
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Symptomatic
Duration >14 days
Neurological involvement
Acquisition of HIV from an index case with
late-stage HIV-1 disease
Factors in Faster Progression of
AIDS
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Virologic
• Infection with SI viral strain
• Persistent p24 antigenemia
• Higher HIV RNA viremia following
seroconversion
Re-infection with HIV
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Doctors in Ottawa, Canada document a case
of re-infection of a HIV (+) patient with a
different strain of HIV.
The patient had sex with another HIV (+)
patient and picked up a new virulent strain..
Therapy stopped working.
Person got progressively worse
Re-infection with HIV
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The patient’s virus level increased without
explanation.
His immune system got weaker suddenly.
This confirms what doctors have long
suspected.
Myth: two HIV(+) people having sex will
not acquire each other’s virus.
Factors in Faster Progression of
AIDS
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Immunologic
• Low antibody titer to p24
• High antibody titer to gp120
• Presence of specific anti-HIV-1 IgM and IgA
after infection
• Immunodeficiency at the time of infection
• Persistently low CD4+ cell count
Neurological abnormalities
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Abnormalities seen in 60% of AIDS
patients
Early
• Acute encephalitis
• Acute meningitis
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Late
• HIV dementia
• Vacuolar myelopathy
Neurological abnormalities
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Continued
• Chronic meningitis
• Inflammatory demyelinating polyneuropathy
• Distal sensory neuropathy
• Stocking-glove impairment
• Myopathy
• Mononeuropathy multiplex
Neurological abnormalities
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Seen in 90% at autopsy of AIDS patients
Pathology
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Gliosis of cerebral sub-cortical nuclei
Focal necrosis of white and gray matter
Perivascular inflammation
Enlargement of oligodendrocyte nuclei
Microglial nodules
Multinucleated giant cells - CPE
Demyelination of white matter
AIDS Dementia
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Stage 0 - normal
Stage 0.5 - sub-clinical or equivocal
• Minimal or mild
• No impairment of work or daily activities
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Stage 1 - mild
• Unequivocal intellectual or motor impairment
• Able to do all but the most demanding work
AIDS Dementia
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Stage 2 - moderate
• Cannot work or perform demanding tasks
• Capable of self care
• Ambulatory but may need one prop
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Stage 3 - severe
• Major intellectual disability
• Cannot walk unassisted
AIDS Dementia
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Stage 4 - end stage
• Nearly vegetative
• Rudimentary cognition
• Para- or quadriplegic
HIV - AIDS Testing
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Culture in PBMC’s
Antibody detection
• ELISA
• Western blot
• PCR
• RT or p24
• HIV Ab or p24
• HIV Ab or ds DNA
• Transcribed DNA
Treatment - Antiviral Compounds
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Nucleoside RT inhibitors
• Chain terminators
• Zidovudine (AZT)
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Tat antagonists
• Inhibit the Tat gene which stimulates
transcription of HIV
Treatment - Antiviral Compounds
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Non-nucleoside RT inhibitors
• Bind to the enzyme active site
• HIV-1 only
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Protease inhibitors
• Block maturation
Guidelines for Treatment
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HAART
• “Highly active antiretroviral therapy”
• Cocktail of antiviral drugs
• Each component hits a separate step in the virus
replication cycle
• Multiple drugs used at once helps prevent
resistance
Guidelines for Treatment
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Adult patients in earliest stages of disease
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One HIV protease inhibitor
Two nucleoside analog inhibitors of RT
DO NOT use one drug at a time
Monitor regularly for virus and CD4+ levels
Change two drugs as soon as treatment appears
to be failing
Guidelines for Treatment
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Treatment should be aggressive
• Goal is to reduce virus to undetectable levels
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These “cocktails” are expensive
• About $15,000 a year
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Patients in more advanced disease
• Three drug “cocktails”
• Avoid any drug previously used in this patient
Guidelines for Treatment
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For pregnant women
• Zidovudine reduces transmission from mother
to child with the following regimen
• Newborn cases now down to 500 per year
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Begin treatment at 14-34 weeks gestation
Continue throughout the pregnancy
Step up IV doses during delivery
Treat newborn within 12 hours and for 6 weeks
Immune Based Therapies
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Improve immunity for prevention of
opportunistic infections
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Passive immunization
Active immunization
Cytokines
Cytokine antagonists