Transcript Human Immunodeficiency Virus

Human Immunodeficiency Virus
By: Trista Kleppin & Iqra Choudary
What is HIV?
• A retrovirsus that impairs the immune system
by destroying CD4 positive T lymphocytes and
leads to AIDS.
HIV Structure
Pathogenesis: Binding
• Gp120 binds CD4
T cells via CXCR4
and the coreceptor CCR5
• After binding a
conformational
change occurs to
allow…
Pathogenesis: Internalization
• Gp41 inserts into
the target cell’s
membrane
• Fusion occurs
• Viral entry into
host cells
Pathogenesis: DNA Synthesis
• Virus uncoats
• Virus’ reverse
transcriptase
converts viral
RNA to dsDNA
Pathogenesis: Integration
• Viral integrase
transports the
dsDNA into the
nucleus
• The ends of the
dsDNA are
cleaved to make
sticky ends
• Integrated into
host DNA
Pathogenesis: Replication
• Host cell
replication leads
to replication of
the incorporated
viral segment
• Protease cleaves
the precursor
polyproteins 
new reverse
transcriptase +
protease
Pathogenesis: Dissemination
• New viral
products are
assembled in the
cytoplasm
• Nucleocapsid
surrounds RNA +
viral proteins
• Virus released
into system via
budding
Transmission Routes
• Sexual Contact
– UNPROTECTED SEX
– Male to male risk 0.3%
– Male to female risk 0.2%
– Female to male risk 0.1%
– Transmission rates higher when HIV negative
partner has active STD lesions
• Syphilis
• HPV
Transmission Routes
• Blood – risk 0.3%
– IVDA
– Blood tranfusions
– Needle Sticks
• Vertical – risk 15-40%
– In utero
– At delivery
– Breast milk
– Risk can be lowered to 1% if mother started on
medications & baby delivered via C-section
2007 U.S. HIV Transmission Data
26% Female
74% Male
2007 U.S. Trends
Acute HIV Syndrome
• Occurs in 40-70% of HIV positive patients
• Symptoms start 3-6 weeks after infection
• Patient may complain of
– Fever
– Myalgia
– Rash
– Pharynigitis
– Headache
Acute HIV Syndrome con’t
• Symptoms usually
resolve in 1-2 weeks
• Clinical latency period
can last 7-10 years
– Patient has no
symptoms
Past Medical History
• Any history of TB?
• Any history of blood transfusions?
• Immunization history
– BCG
– Hepatitis A & B
Social History
• Drug usage
• Occupation
– Healthcare worker
– Prostitute
– Especially IVDA
• Recent Travel
2007 World Wide HIV Prevalence
Social History con’t
• Sexual history
– Any known HIV positive partners?
– Any unsafe sexual practices?
– Any history of STDs?
– Number of sexual partners
– Gender of sexual partners
– Last negative HIV test
Review of Systems
• General: weight loss, night sweats, anorexia,
fever
• HEENT: vision changes, headaches, oral lesions,
enlarged lymph nodes
• Lungs: cough, SOB, dyspnea on exertion
• Abd: N/V, diarrhea, rectal pain
• Genital: lesions, females: abnormal vaginal
bleeding
• Skin: rashes, pigmented lesions, nodules
• Neuro: numbness, tingling, memory changes
Physical Exam
• No physical findings are
specific to HIV
• Looking for signs of
opprotunistic infections
that are common in HIV
• Vitals: ↓ weight, ↑RR
• Skin/nails: rash, fungal
infection
• HEENT:
–
–
–
–
–
Retinitis
Oral sores
Oral thrush
Oral hairy leukoplakia
Lymphadenopathy (may also
be present in ASx patients)
Normal
Retinitis
Physical Exam con’t
• Lungs: ↓breath sounds unilaterally, dulled
percussion unilaterally
• Abdomen: tenderness, hepatomegaly,
splenomegaly
• Genital: STD lesions
– Females: pap smear, vaginal candiasis
• Neuro: dementia (MMSE), ↓peripheral
sensation, hyperreflexia
Follow Up Recommendations
• Routine follow up every 6 months
– Complete Review of Systems
– HIV Dementia Scale/MMSE
• Opthalmology visit every 3-6 months if CD4
<100
• Skin examination every 6 months
• Pap smear 2 times the 1st year diagnosed
– If both normal then annual exam there after
Diagnosis
• The diagnosis of HIV infection is established by
one of the following methods:
– detecting antibodies to the virus
– detecting the viral p24 antigen
– detecting viral nucleic acid (NAT)
– culturing HIV
Serologic Response
The serologic tests for HIV infection are based
upon detection of IgG antibody against HIV-1
antigens in serum. These HIV antigens include
p24 (a nucleocapsid protein) and gp 120 and gp
41 (envelope proteins).
• Antibodies to gp41 and p24 antigens are the
first detectable serologic markers following
HIV infection
• IgG antibodies appear 6 to 12 weeks
following HIV infection in the majority of
patients and by six months in 95 percent of
patients
• IgG antibodies to HIV generally persist for
life.
• Positive tests should be confirmed with
Western blot assays
Rapid Tests
•
•
•
•
Advantageous for occupational or nonoccupational HIV exposures, women who present in
labor without prior HIV testing, and patients who are unlikely to return for results
All positive rapid HIV test results must be confirmed with standard EIA antibody and Western
blot testing
Testing is complete if the rapid test is negative, unless there is clinical suspicion of acute HIV
infection
The patient with an indeterminate result should have repeat testing in one to two months
with rapid or standard serologies
Combination Antibody-Antigen Testing
• Fourth generation tests are distinguished
from the antibody tests above by their ability
to detect both antibody and p24 antigen
• The advantage of these assays is in their
ability to detect HIV p24 antigen during acute
infection when antibody formation may not
yet be detected ("window period of acute HIV
infection”)
• High Sensitivity and Specificity
Viral Detection
• Other methods to establish HIV infection include viral
isolation through polymerase chain reaction techniques,
branched chain DNA testing, or nucleic acid sequence-based
amplification (NASBA)
• Limitations include cost, the requirement for venipuncture
and more lab technology, and time interval between sample
collection and test results.
• None of the above tests are considered superior to routine
serologic testing
• Viral detection is useful in the diagnosis of neonatal HIV
infection (HIV RNA PCR), in patients with indeterminate
serologic tests, or in those who may be in the "window
period" of HIV seroconversion
Treatment
• The goals of ART are too;
– prolong life and improve its quality
– restore and preserve immunologic function (as
measured by CD4 count)
– Maximally suppress the viral load
Although eradication of HIV infection is not
achievable with current management approaches,
ART has resulted in significant reductions in HIVrelated morbidity and mortality.
Entry Inhibitors
HIV entry into a human cells requires the
following steps in sequence:
1. The binding of HIV surface protein gp120 to
the CD4 receptor
2. A conformational change in gp120, which
both increases its affinity for a coreceptor and
exposes gp41
3. The binding of gp120 to a coreceptor either
CCR5 or CXCR4
4. The penetration of the cell membrane by
gp41, which approximates the membrane of
HIV and the T cell and promotes their fusion
5. The entry of the viral core into the cell
Entry inhibitors work by interfering with one
aspect of this process
Approved Agents:
• Maraviroc (Celsentri) binds to
CCR5, preventing an interaction
with gp120. It is also referred to
as a "chemokine receptor
antagonist" or a "CCR5 inhibitor“
• Enfuviritide (Fuzeon) binds to
gp41 and interferes with its
ability to approximate the two
membranes. It is also referred to
as a "fusion inhibitor"
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
The mode of action of NRTIs and NtRTIs is
essentially the same;
• Analogues of the naturally occurring
deoxynucleotides needed to synthesize
the viral DNA
• Compete with the natural
deoxynucleotides for incorporation into
the growing viral DNA chain
• Unlike the natural deoxynucleotides
substrates, NRTIs and NtRTIs lack a 3'hydroxyl group on the deoxyribose
moiety. As a result, following
incorporation of the drug, the next
incoming deoxynucleotide cannot form
the next 5'-3' phosphodiester bond
needed to extend the DNA chain.
• When an NRTI or NtRTI is incorporated,
viral DNA synthesis is halted, a process
known as chain termination
Zidovudine
Didanosine
Zalcitabine
Stavudine
Lamivudine
Abacavir
Emtricitabine
Entecavir
Apricitabine
Tenofovir
Adefovir
Non-nucleoside Reverse Transcriptase Inhibitors
• NNRTIs block reverse
transcriptase by binding at a
different site on the enzyme,
compared to NRTIs and NtRTIs
• NNRTIs are not incorporated
into the viral DNA but instead
inhibit the movement of
protein domains of reverse
transcriptase that are needed
to carry out the process of
DNA synthesis
• Non-competitive inhibitors
Efavirenz
Nevirapine
Delavirdine
Etravirine
Protease Inhibitors
• Prevent viral replication
by inhibiting the activity
of proteases (e.g.HIV-1
protease) used by the
viruses to cleave
nascent proteins for
final assembly of new
virons
• - “avir”
Long-Term Complications of Treatment
• The decision to initiate ART is complex and
requires discussion between patient and
physician due to long term drug toxicities
• Following initiation of ART, patients should
return in two to four weeks to assess for drug
toxicity or adherence problems and to recheck
the HIV viral load and CD4 count
Dyslipidemia — common adverse effect of treatment. It has been reported with protease
inhibitors
Glucose intolerance/diabetes mellitus — important toxicity associated with ART, especially PI’s.
Patients starting on ART should have a fasting glucose at baseline, and at three to six months later
and at least annually thereafter
Coronary artery disease — PI therapy may be associated with an increased risk of coronary
artery disease
Lipodystrophy — fat maldistribution can occur as a loss of peripheral fat (lipoatrophy: facial,
extremity, and buttocks thinning), increase in central adiposity (lipohypertrophy: increased
abdominal girth, prominent dorsicocervical fat pad), or both
Peripheral neuropathy — mainly sensory and involves the lower extremities, has been reported
with didanosine and stavudine and with HIV infection itself. These nucleoside reverse
transcriptase inhibitor (NRTI) drugs should be avoided in patients with a history of peripheral
neuropathy and should never be used in combination
Lactic acidosis — NRTIs may lead to mitochondrial toxicity as a result of their interference with
the function of DNA-polymerase
Hepatic, renal, and bone marrow toxicity — Hepatotoxicity can occur with any antiretroviral
drug but has been reported most often with NNRTIs and PIs. Patients on ART should have hepatic
function tests monitored every three to four months
Bone disorders — Osteopenia and osteoporosis have been reported in higher frequency in HIVinfected patients , especially due to PIs
Prophylaxis of Opportunistic Pathogens
Refer to handout
Question
A 27-year-old sexually active African-American woman presents
to the emergency department complaining of low-grade fevers,
chills, night sweats, and burning chest pain that is worse with
swallowing. The physician immediately notices white patches
consistent with oral candidiasis on the patient’s tongue. She says
she has never had this before. Further examination reveals
extension of thrush into the esophagus. Which of the following
conditions does the patient most likely have?
(A) Cardiac chest pain
(B) HIV
(C) Mallory-Weiss tear
(D) Nothing; healthy patients can get candidal esophagitis
(E) Severe combined immunodefi ciency syndrome
(F) Vaginal candidiasis
Answer
The correct answer is B. Oral candidiasis most often
presents as white patches in the oral mucosa.
Candidiasis is present only in the
immunocompromised, which would make HIV
the most likely comorbidity in this case.
Treatment is usually simple nystatin swish and
swallow. Prognosis is excellent and candidal
thrush usually resolves without complications as
long as the condition is appropriately diagnosed
and treated.
Answer A is incorrect. Candidal esophagitis is not
associated with cardiac chest pain. Both may
present with chest pain, but the history states
that the patient’s chest pain is retrosternal and
worse with swallowing, suggesting esophagitis.
No other symptoms are suggestive of cardiac
chest pain.
Answer C is incorrect. Mallory-Weiss tear is a
condition producing hematemesis following
esophageal mucosal tear. It is predisposed by
vomiting, coughing, and retching. It is certainly
in the differential for esophagitis, but it is not
the correct answer here.
Answer C is incorrect. Mallory-Weiss tear is a
condition producing hematemesis following
esophageal mucosal tear. It is predisposed by
vomiting, coughing, and retching. It is certainly
in the differential for esophagitis, but it is not
the correct answer here.
Answer D is incorrect. Candidiasis does not infect
the esophagus in immunocompetent hosts.
Answer E is incorrect. Severe combined
immunodeficiency syndrome (SCID) is a
condition in which children have a total
deficiency of T and B lymphocytes, resulting in
immunocompromise from birth. This patient
could have SCID; however, this condition is less
likely than HIV and would have affected the
patient from birth.
Answer F is incorrect. Candidal esophagitis and
vaginal candidiasis are separate entities. The
former is seen only in immunocompromised
hosts, while the latter can be seen in healthy
females.
Question
•
A 29-year-old man presents to a community health clinic with a week-long history
of painful swallowing. The pain is located retrosternally and occasionally radiates
into the oropharynx. He denies weight loss, hematemesis, or change in stool color.
He has a known history of human immunodeficiency virus (HIV) infection and his
last CD4 count was 48 cells/mm3. A barium swallow is performed and
demonstrates multiple large, deep linear ulcers. Endoscopy is performed with
brushings and biopsy. Histopathology reveals a paucity of cells with enlarged and
smudged nuclei that are intensely eosinophilic. What is the most likely cause of
this patient's symptoms?
a. Candida albicans
b. Cytomegalovirus (CMV)
c. Eosinophilic esophagitis
d. Gastroesophageal reflux disease (GERD)
e. Herpes simplex virus (HSV)
Answer
b. Cytomegalovirus (CMV)
• This patients CD4 count is <50
• Esophegeal ulcers in HIV patients are most
commonly due to CMV
• Large intensely eosinophilic nucleus
References
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Davidson’s Principles and Practice of Medicine
Rubin’s Pathology
Harrison's Principles of Internal Medicine, 17e
CDC website
First Aid Q&A for USMLE Step 2CK
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