Download Human Immunodeficiency Virus (HIV) presentation

Human Immunodeficiency Virus (HIV)
Gayane Arutunyan
Monica Brown
David Yang
Patient
 28 year old male
 Bad case of thrush (oral candidiasis)
 Low grade fever
 Lost 20 pounds in the last year without dieting
 Serious bouts of diarrhea
•
Stool Sample tested positive for Giardia lamblia.
 Difficulty breathing
•
Radiographic examination showed bilateral infiltrate
(characteristic of Pneumocystosis carinii pneumonia)
Radiographic Results
(A.D.A.M., 2006)
Patient
 28 year old male
 Bad case of thrush (oral candidiasis)
 Low grade fever
 Lost 20 pounds in the last year without dieting
 Serious bouts of diarrhea
•
Stool Sample tested positive for Giardia lamblia.
 Difficulty breathing
•
Radiographic examination showed bilateral infiltrate
(characteristic of Pneumocystosis carinii pneumonia)
 Heroin addict and admits to sharing needles at a “shooting
gallery”
Human Immunodeficiency Virus
(HIV)
gp120
gp160
Icosahedral or
Wedge-shaped
Nucleocapsid
gp41
Reverse
Transcriptase
single stranded
(+) sense RNA
(NIH, 2005)
Lipid Membrane
HIV genome
Two copies (+) ss RNA
(Dimmock, et. al, 2007)
Types of HIV
 Two species of HIV infect humans:
1. HIV-1
•
•
•
More virulent, relatively easy to transmit
Majority of HIV infections globally
3 types of HIV-1: (based on alterations in env gene)
–
Clades M, N, and O
2. HIV-2
•
•
Less transmittable
Largely confined to West Africa
(Gao, et. al; 1999)
(Keele, et. al; 2006)
(Reeves, et. al; 2002)
(Thompson, et. al; 2002)
Laboratory Tests
 Enzyme Linked Immunosorbent Assay
(ELISA)
• Direct : Tests for the virus
• Indirect : Tests for antibodies to the virus
Indirect ELISA
Rinse
HIV Antigen
Rinse
Patient’s serum
Rinse
NoColor
ColorChange
Change
Enzyme-labeled
antihuman IgG
Laboratory Tests
 Enzyme Linked Immunosorbent Assay
(ELISA)
• Direct : Tests for the virus
• Indirect : Tests for antibodies to the virus
 Western Blot Analysis
•
•
Direct : analyze samples for specific protein(s)
Indirect : analyze samples for antibodies against
a specific protein(s)
Indirect Western Blot Analysis
HIV – Western Blot Results
gp160 = viral envelope precursor (env)
gp120 = viral envelope protein binds to CD4
p31 = reverse transcriptase (pol)
p24 = viral core protein (gag)
HIV (+) serum HIV (-) serum
(Univ. of Arizona, 1996)
Patient Risk Assessment
 High Risk Behaviors:
•
•
•
•
Sharing of infected drug injection needles/syringes
Accidental needle stick (healthcare professionals)
Unprotected sex with infected individual
Blood transfusions/Organ transplants
»
•
•
Rare, only occurs in underdeveloped countries with
inadequate blood donor testing programs
Transmission from infected mother-to-fetus during
pregnancy or delivery
Transmission from breast milk of infected mother to her
baby
Prevention of HIV Infection
 Known Methods of Preventing HIV Infection:
•
Avoid sexual contact with infected individuals
•
Avoid sharing needles/syringes that could be
contaminated with HIV
•
Avoid any type of contact with the bodily fluid of an
infected individual
Prevention of HIV Infection
 New Methods for Prevention of HIV:
•
•
•
•
Intravaginal lime or lemon juice to kill the HIV virus
before entry
Intravaginal oestrogen: Karotinizing the vagina with
estrogen
Male circumcision: Removal of the inner foreskin
removes the main site of HIV entry into the penis,
resulting in a sevenfold reduction in susceptibility to
infection
Post-coital penile hygiene: Wiping the penis immediately
after intercourse with lime or lemon juice or vinegar
should kill the virus before it has had a chance to infect.
Immunological Basis for
Opportunistic Infection
 HIV targets cells that express CD4 and can infect macrophages, dendritic
cells, and activated T cells
 During the non-symptomatic phase of HIV infection, HIV has a low affinity
towards T cells and higher affinity towards macrophages → slow death
rate of T cells
 Once the virus becomes lymphotropic, it begins to infect activated T cells
far more efficiently due to increased affinity for CD4

Functional T cell levels begin to decrease, eventually to a point where
the T cell population is too small to recognize the full range of Ags that
could potentially be detected
 The lack of full Ag recognition → core symptoms of acquired immune
deficiency syndrome (AIDS). CD4 T cell depletion during AIDS allows
various pathogens to escape T cell recognition, thus allowing
opportunistic infections that would normally elicit a helper T cell
response to bypass the immune system
Immunological Basis for
Opportunistic Infection
 Nef protein – advances the endocytosis and degradation of
cell surface proteins, including CD4 and MHC proteins
•
Downregulates expression of host CD4
•
Downregulates expression of host MHC class I molecules
»
•
Induces phosphorylation of MA proteins to increase viral
infectivity (increased viral replication)
»
•
MHC class I molecules function to present peptide fragments to
cytotoxic T cells to destroy virally infected cells.
MA and Vpr proteins aid in facilitating the transport of HIV preintegration complex across nuclear membrane.
Alter T cell signaling to promote viral replication.
Opportunistic Infections
CD4 Count
200-500/μL
Diseases
Pneumonia (usually caused by bacteria)
Tuberculosis in the lungs
Oral or vaginal yeast infections
Shingles (viral skin infection)
Oral hairy leukoplakia
Kaposi’s sarcoma
100-200/μL
All of the above plus:
Pneumoniadue to Pneumocystis carinii (PCP)
Chronic diarrhea
50-100/ μL
All of the above plus:
Encephalitis (usually due to toxoplasmosis)
Esophagitis due to yeast or viruses
Meningitis (usually due to cryptococcus)
Opportunistic Infections
CD4 Count
Diseases
(50-100/µL
Continued)
Tuberculosis outside the lungs
Chronic herpes simples virus (HSV infection)
Primary brain lymphoma
<50 /µL
All of the above, plus:
Widespread infection due to Mycobacterium avium complex
Retinitis, diarrhea, encephalitis due to cytomegalovirus
Epidemiology
 The virus was first successfully identified and classified in 1981.
•
The appearance of rare diseases amongst HIV infected persons first alerted
scientists to the then unknown virus.
 At end of 2003 in the U.S. 1,039,000 - 1,185,000 persons infected
with HIV/AIDS
 Global (2006 statistics): 39.5 million infected with HIV/AIDS
 4.3 million new infections in 2006; 2.8 million (65%) of these were in
sub-Saharan Africa
 Increases in Eastern Europe and Central Asia, where there may have
been a more than 50% rise in infection rates since 2004
 In 2006, 2.9 million deaths due to AIDS-related illnesses
2003
HIV and Disease
 Human Immunodeficiency Virus (HIV) has an incubation period of about 10 years and
eventually leads to Acquired Immunodeficiency Syndrome (AIDS), resulting in the
impairment of the immune system.
 This can lead to death from infections, secondary diseases from opportunistic bacteria
and/or viruses that are usually harmless to people, or many different types of cancers.
 Common diseases associated with HIV infection:
•
•
•
Kaposi's sarcoma (KS)
Pneumocystis carinii pneumonia (PCP)
Mycobacterium avium complex (MAC)
Early Symptoms:
 Most don’t exhibit symptoms when first infected
 However, may have flu-like symptoms (fever,
headache, tired, enlarged lymph nodes) 1-2 months
after exposure
 Very infectious during this period
HIV and Disease
Later Symptoms:
 More sever symptoms may not appear until after 10yrs, however this
varies with each individual
 Decline in number of CD4 + T cells
 The most advanced stage of AIDS is classified as having < 200 CD4+ T
cells/cubic millimeter of blood (in healthy adults CD4+ T-cell counts =
1,000+)
 Onset of AIDS is characterized by:
•
•
•
•
•
•
•
•
•
•
•
weight loss,
fevers/sweats,
fatigue
rashes/flaky skin,
persistent yeast infections,
Pelvic inflammatory disease in women will not respond to treatments,
short-term memory loss,
frequent and severe herpes infections,
shingles
coma
deaths
Precautions
Pre-Exposure
 Assume any patient’s blood and
other bodily fluids are potentially
infectious
 Protective barriers
 Hands and all other skin surfaces
must be immediately washed after
any contact with blood or body fluids
 Extra precaution must be taken in
the handling and proper disposal of
any sharp instruments used on a
patient
Post-Exposure
In post-exposure cases, the
Center for Disease Control
and Prevention (CDC)
recommends the post
exposure prophylaxis (PEP)
Antiretroviral medications (Tenofovir
disoproxil fumarate and emtricitabine)
administered to HIV-infected women
during labor and delivery has shown
~50% reduction in the risk of mother-tochild transmission
Antiretroviral regimens have been
shown to be associated with an 80%
reduction in risk of HIV infection among
healthcare personnel following needle
sticks and other accidental exposures,
when treatment is initiated promptly
Treatments
 Reverse Transcriptase (RT) Inhibitors – interrupt early stage of
viral replication to slow spread of HIV in body and delay start of
opportunistic infections
1) Nucleoside/nucleotide RT inhibitors
•
•
Abacavir
Insert faulty DNA building blocks into HIV genome
Prevents completion of DNA chain → no replication
Lamivudine Stavudine Trizivir Zalcitabine Zidovudine
Combivir
Didanosine
2) Non-nucleoside RT inhibitors
•
•
Bind to reverse transcriptase and prevents reverse transcription
May slow the spread of HIV in the body and delay the start of
opportunistic infections.
Delavirdine Efavirenz Nevirapine
Treatments
 Protease Inhibitors – interrupt late stage of viral replication in
the HIV life cycle
Amprenavir
Indinavir
Kaletra
Nelfinavir
Ritonavir
Saquinavir Fortovase
 Side Effects: nausea, diarrhea, gastrointestinal symptoms, serious
effects from interaction with other drugs
 Fusion Inhibitors – new class of drugs
•
•
•
•
•

Fuzeon (enfuvirtide or T-20) interferes with HIV-1’s ability to enter the
cell by blocking fusion of the virus to the host cell membrane
HIV cannot enter and infect immune cells
Designed to be used in combination with other anti-HIV treatments
reduces the level of HIV infection in blood
may be effective against HIV resistant to current antiviral treatments
Side Effects: pneumonia, trouble breathing, low bp, chills/fever, skin
rash, blood in urine, vomiting
Treatments
 HAART
• Treatment has significantly reduced number of deaths from AIDS in
the U.S.
• Reduces the amount of virus circulating in blood to nearly
undetectable levels, although HIV is still present by hiding places such
as the brain, lymph nodes, testes, & retina of the eye
 Side Effects: severe; decrease in RBCs or WBCs, inflammation of
pancreas, painful nerve damage, even death in some cases
Vaccines
 Currently, no vaccines approved for use by the FDA
 Two types in development:
1. Therapeutic Vaccine - intended to boost the
immune systems of those already infected
2. Preventive Vaccine – intended to generate
an immune response in an uninfected
person to prevent future infection
Possible Targets of a Theoretical HIV Vaccine:
1. gp120, gp160 and gp41 viral surface proteins
•
to prevent it from binding to the host cell receptor CD4.
2. Cyclophilin A
•
•
At the cell surface – to block from binding to the heparin sulfate
receptors
Within the cytoplasm – to keep from expanding the viral core.
»
Without expansion of the viral core, reverse transcription cannot occur.
3. Reverse transcriptase
•
Unable to synthesize new copies of the viral genome.
4. CCR5 (chemokine) receptor
•
Cleavage – to inactivate the receptor.
»
»
»
Approximately 13% of people of northern European descent have a
naturally occurring deletion of 32 base pairs in the CCR5 gene results.
This mutant CCR5 receptor never reaches the surface of their cells.
Homozygotes for this mutation (1-2% Caucasians) have a resistance to HIV
infection.
Preventive HIV Vaccines Under Development:
1. Subunit vaccines – "component" or "protein" vaccines that
contain an individual viral components rather than the whole virus
•
•
The subunits are made through genetic engineering and administered to
induce an anti-HIV immune response
The weak response however may not prevent future infections
2. Recombinant vector vaccines – use of non-HIV viruses that do
not cause disease in humans or have been rendered unable to
cause disease (attenuated)
•
•
•
viruses are used as vectors carry copies of HIV genes into human cells, in
which HIV proteins will be produced
HIV proteins can stimulate an anti-HIV immune response. The response
may be stronger since the recombinant vector vaccines delivers several
HIV genes
Vectors being studied for use in HIV vaccines are ALVAC (canarypox virus),
MVA (type of cowpox virus), VEE (normally a horse virus), and
adenovirus-5 (human virus; usually doesn’t cause serious disease)
Preventive HIV Vaccines Under Development:
3. DNA vaccines – introduce HIV genes into the body, but don’t rely
on a virus vector
•
“Naked" DNA containing HIV genes injected directly into body so that
the cells will take it up and produce HIV proteins
•
HIV proteins will induce immune response against HIV
Prime-Boost Vaccination Strategy
Use one type of vaccine, then administer a second type later to stimulate
different parts of the immune system to boost up the overall defense of the
body
Who Can Benefit from HIV
Vaccines?
 Healthcare professionals
 Blood/organ recipients (especially in
underdeveloped countries)
 Countries where a significant number of the
population has people infected with HIV and has
poor health care
 Individuals in high risk groups
References
1. Dimmock, N.J., Easton, A.J., and K.N. Leppard. Introduction to Modern Virology, 6th Edition.
Blackwell publishing Ltd. 2007.
2. Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenburg, C. M., Michael, S. F., Cummins, L. B., Arthur,
L. O., Peeters, M., Shaw, G. M., Sharp, P. M., and Hahn, B. H. (1999). "Origin of HIV-1 in the
Chimpanzee Pan troglodytes troglodytes". Nature 397 (6718): 436-441. doi:10.1038/17130. PMID
9989410.
3. Keele, B. F., van Heuverswyn, F., Li, Y. Y., Bailes, E., Takehisa, J., Santiago, M. L., Bibollet-Ruche, F.,
Chen, Y., Wain, L. V., Liegois, F., Loul, S., Mpoudi Ngole, E., Bienvenue, Y., Delaporte, E., Brookfield, J.
F. Y., Sharp, P. M., Shaw, G. M., Peeters, M., and Hahn, B. H. (2006). "Chimpanzee Reservoirs of
Pandemic and Nonpandemic HIV-1". Science Online 2006-05-25. doi:10.1126/science.1126531
4. McQueen, Nancy. Microbiology 401 lectures material. California State University, Los Angeles. 2007
5. MedLinePlus. "HIV ELISA/western blot." U.S. National Library of Medicine. Last accessed April 16,
2007. http://www.nlm.nih.gov/medlineplus/ency/article/003538.htm
6. Reeves, J. D. and Doms, R. W (2002). "Human Immunodeficiency Virus Type 2". J. Gen. Virol. 83 (Pt
6): 1253-1265. PMID 12029140
7. Thomson, M. M., Perez-Alvarez, L. and Najera, R. (2002). "Molecular epidemiology of HIV-1 genetic
forms and its significance for vaccine development and therapy". Lancet Infect. Dis. 2 (8): 461-471.
PMID 12150845
8. http://www.niaid.nih.gov/factsheets/hivinf.htm
9. http://hivinsite.ucsf.edu/InSite?page=kb-02&doc=kb-02-01-01
10. http://www.cdc.gov/hiv
11. http://aidsinfo.nih.gov/ContentFiles/HIVPreventionVaccines_FS_en.pdf
12. http://www.cdc.gov/hiv/resources/factsheets/At-A-Glance.htm
13. http://www.globalrph.com/hivupdate.htm
14. http://www.tpan.com/publications/pa/jan_feb_06/fuzeon.shtml
15. http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf
16. http://www.who.int/hiv/topics/me/en/index.html
Picture references
1. Dimmock, N.J., Easton, A.J., and K.N. Leppard. Introduction to Modern Virology,
6th Edition. Blackwell publishing Ltd. 2007.
2. http://wildiris3.securesites.net/cms_prod/files/course/192/WAHIV4_2007_fig1.jp
g
3. http://www.eduwhere.com/images/lab_goggles.jpg
4. http://www.osha.gov/needlesticks/biohazard-sample2.jpg
5. http://www1.istockphoto.com/file_thumbview_approve/2209865/2/istockphoto_
2209865_hiv_negative.jpg
6. http://www.inmarkinc.com/images/hinew02.jpg
7. http://www.ipngos.org/images/vaccine.jpg
8. http://www.who.int/hiv/facts/en/hiv_global2003.jpg
9. http://www.stanford.edu/group/virus/retro/2005gongishmail/hiv2.jpg
10. http://pathmicro.med.sc.edu/images/global.gif
11. http://www.metrokc.gov/HEALTH/apu/healthed/background/global.gif
12. http://www.niaid.nih.gov/factsheets/howhiv.htm
13. http://www.biology.arizona.edu/immunology/activities/western_blot/west2.html
Questions?