The Human Immunodeficiency Virus (HIV) will eventually cause Acquired Immunodeficiency
Syndrome (AIDS), where the immune system of the body is severely damaged and very prone to other
types of infections.
● What are Viruses?
○ Viruses are smaller than bacteria. Sizes range from 20 nm to 300nm or 1.7 kb to 33KB.
(Carter 5)
○ They can replicate only within suitable host cells as they depend on the hosts for
most of their requirements including amino acids (the building blocks for proteins)
and nucleosides (which form nucleotides, which form DNA), and protein-synthesizing
machinery and energy. Viruses are therefore parasites of cells.
○ Viruses infect all types of organisms, from animals and plants to bacteria and minuscule
cells (archaea).
○ Viruses may be comprised only of protein and nucleic acid.
○ The nucleic acid component of viruses is RNA or DNA that can be double stranded or
single stranded.
○ The nucleic acid of the virus contains its genetic information.
○ Viruses are assembled from multiple copies of one or more kinds of identical
protein subunits.
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The viral genome is enclosed in a protein coat known as a capsid.
There are two general types of capsid structures. One type displays helical symmetry
and the other type displays icosahedral symmetry. Capsids are formed from identical
protein subunits called capsomeres. Many viruses with helical symmetry are enclosed
within lipid envelopes.
An icosahedron is a regular 20-sided polygon, where each face is an equilateral triangle.
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It has 12 vertices. Each face of the icosahedron has an identical number of protein
subunits.
○ A complete viral particle outside the host cell is known as a virion.
What do we know about the Human Immunodeficiency Virus?
○ HIV was discovered in 1983
○ HIV-1 is globally dispersed, causes over 99% of HIV infections, and is usually fatal
○ HIV-1 is diploid and contains two identical molecules of positive sense single strand
RNA. Its genome conforms to the basic oncovirus plan with the standard gene order 5’gag-pol-3’, but is complicated by a number of additional regulatory genes (Dimmock
315).
○ HIV-2 is much less pathogenic and is largely restricted to West Africa (Dimmock 313)
○ When an individual’s CD4 T cell count falls below 200 cells /mm3, or below a CD4
percentage of about 14%, they are diagnosed as having Acquired Immune Deficiency
Syndrome (AIDS).
What does HIV consist of?
HIV consists of a piece of RNA wrapped in a small number of coat proteins and a few lipids
The HIV genome has only 9 different genes (Clark 110)
○ Six of these are small genes coding for elements that regulate HIV reproduction inside
the host CD4+ cells
○ The other three are large genes coding for complex proteins:
○ gag, which consists of three smaller proteins used to build the basic structure of the
virion
○ env, which makes gp120 and gp41
○ pol, which consists of protease (this cuts the next round of newly made complex
proteins), reverse transcriptase (this converts the virus RNA to cDNA), and nuclease
(this cuts open the host DNA, inserts the virus cDNA, and closes the DNA cuts)
18 of the first 19 HIC isolates taken from AIDS patients were immunologically different because
the coat proteins of HIV that are detected by antibodies are mutating at an extraordinarily high
rate (Clark 115)
○ The flu virus is similar but mutates more slowly and is easier for the body to get rid of.
HIV is a class VI virus and is a member of the lentivirus genus of the retrovirus family.
Norkin 45)
● What is Class VI virus? (
○ It is a group of viruses classified under the Baltimore Classification Scheme.
○ David Baltimore grouped viruses into classes whose members had a common basic
strategy of dealing with viral genome expression and replication.
○ This framework originally allowed formation of 6 classes. Now a 7th class also exists.
● What is a retrovirus? (Norkin 48-49)
○ Retroviruses have a single-stranded RNA genomes of the plus sense, that means the
RNA strand has the same base sequences as the mRNA (but unlike Baltimore class IV
their plus- sense RNA genomes do not serve as mRNAs)
○ Encoding for the enzyme reverse transcriptase enters into the cell with the viral
genome, and hence the enzyme is soon produced.
○ It reverse transcribes the RNA (ribonucleic acid) genome to produce a double-stranded
DNA (deoxyribonucleic acid), which is then integrated into a cellular chromosome.
(instead of DNA transcribing mRNA according to the central Dogma)
○ The integrated viral DNA is referred to as a provirus.
○ It is transcribed by the host cell’s pol II RNA polymerase to generate all retroviral mRNA
molecules and all retroviral progeny RNA genomes as well.
● What is a lentivirus?
○ The lentivirus genus is composed of “slow” viruses; it usually takes about ten years from
infection of HIV to frank AIDS (Dimmock 313).
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HIV directly impacts Helper T-cells or CD4+ T cells that are part of the immune system.
● What are Helper T-cells?
● T helper cells (Th cells) are a sub-group of lymphocytes, a type of a
leukocyte or white blood cell that play an important role in the immune
system.
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There are two kinds of T cells, both of which are developed from stem cells in bone marrow by
the thymus, a glandular organ just above the heart (Clark 9)
The two kinds are: T- helper cells (which are CD4+), and T-killer cells (CD8+)
Mature Th cells express the surface protein CD4 and are referred to as CD4+ T cells.
Helper T cells help activate other cells of the immune system, but themselves have no cytotoxic
or phagocytic activity and cannot kill invading pathogens.
However, CD4+ T cells affect virtually every phase of the immune response, and are involved in
communication between the immune system and the brain (Clark 120)
Helper T cells help both B-cells (another type of lymphocytes), as well as killer T cells. B-cells
require help from a helper T cell in order to proceed to full activation and antibody production.
Killer T cells require helper T cells for functional maturation.
HIV enters its host helper T-cell using its receptor protein CD4.
● How viruses enter an animal cell? (Norkin 42-44)
○ Virus attaches to a specific receptor on the surface of a host cell.
○ Using the receptor- mediated endocytosis pathway, the animal virus genome enters the
host cell.
○ Clathrin- coated pits form in the plasma membrane at the site of the ligand binding to
the receptor.
○ The coated pits mature into coated vesicles that pinch off from the plasma membrane
inwards towards the cell nucleus, with the virus inside the vesicle.
○ The fusion of the acidic lysomsomal content with the endosome (the vesicle), causes
the virus particle to undergo structural rearrangements that can promote release of the
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virus or the genome into the cytosol.
○ However, to cross through the single membrane of the vesicle surrounding the virus
different mechanisms exist in various viruses. Enveloped viruses contain virus-encoded
spike proteins, which are embedded in their envelopes. The low pH of the endosomal
compartment may trigger conformational changes in these spike proteins, which has
the effect of exposing hydrophobic regions, called fusion peptides, on them. The newlyexposed fusion peptides are able to insert into the endosomal membrane. (Norkin 44)
○ The spike proteins undergo further conformational rearrangements that promote the
fusion of the viral envelope and the endosomal membrane.
○ The fusion of the two membranes releases the viral core into the cytosol.
○ Some other viruses carry out fusion at the plasma membrane, at the time of the initial
attachment. The fusion-promoting conformational rearrangements of the spike proteins
are triggered by the interaction of the spike proteins with their receptors at the time of
the attachment.
○ Mechanisms by which nonenveloped viruses breach cellular membranes are still under
research.
How does HIV enter CD4+ T cells?
○ First, glycoprotein (gp120 specifically) on the HIV virus bind to the cell it will infect.
Gp120 specifically recognizes and binds to the CD4 molecule found mostly on CD4 T
cells.
■ CD4 proteins are also found to a lesser extent on macrophages and possible
certain brain cells
■ Gp120 attaches to CD4, twists slightly, revealing 2nd binding molecule, gp41.
Gp41 muct bind with a second co-receptor on the CD4 cell surface known as
fusin or C-C chemokine receptor type 5 (CCR5)
○ With the binding of both gp120 and gp41, to CD4 and CCR5 respectively, the
membranes of HIV and the CD4+ cell fuse and the contents of the HIV virion pass into
the CD4 T cell
○ HIV then begins the process of converting RNA to cDNA. At this point, most of the
mutations occur. Reverse transcriptase (RT) is brought by the HIV virion to convert RNA
to DNA
○ Mutations arise here because the RT enzyme is prone to making mistakes in copying HIV
RNA to DNA and these copy errors are not edited
○ Viral cDNA integrates into the host genome where it is then transcribed into mRNA,
which is translated into proteins that compose the virus
○ New virion makes its way to the surface membrane of the cell, using the cells own
transport machinery. At the surface, it fuses with the cells membrane and gently pushes
out, making a small “bud”. The virion picks up some of the lipids in the CD4 cell’s
membrane to complete its own coat
It is important to know that early knowledge of HIV infection can not only benefit you, but
it can also result in tremendous public health benefits by decreasing risk behaviors that can
transmit HIV to uninfected persons. Even if you are infected you may have several treatment
options available to you that can prolong your life and allow you to continue living a normal
life.
● What determines my status for treatment?
The following laboratory tests performed during initial patient visits can be used to
stage HIV disease and to assist in the selection of antiretroviral (ARV) drug regimens:
• HIV antibody testing (if prior documentation is not available or if HIV RNA is below the
assay’s limit of detection)
• CD4 T-cell count
• Plasma HIV RNA (viral load)
• Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen
(BUN) and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses
• Fasting blood glucose and serum lipids; and
• Genotypic resistance testing at entry into care, regardless of whether ART will be
initiated immediately. For patients who have HIV RNA levels <500–1,000 copies/mL,
amplification of virus for resistance testing may not always be successful.
Source: http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-
treatment-guidelines/36/baseline-evaluation
CDC Classification System for HIV Infection
The CDC categorization of HIV/AIDS is based on the lowest documented CD4 cell count
and on previously diagnosed HIV-related conditions Patients in categories A3, B3, and
C1-C3 are considered to have AIDS.
* Category B Symptomatic Conditions
Category B symptomatic conditions are defined as symptomatic conditions occurring in
an HIV-infected adolescent or adult that meet at least one of the following criteria:
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They are attributed to HIV infection or indicate a defect in cell-mediated immunity.
They are considered to have a clinical course or management that is complicated by HIV
infection.
Examples include, but are not limited to, the following:
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Bacillary angiomatosis
Oropharyngeal candidiasis (thrush)
Vulvovaginal candidiasis, persistent or resistant
Pelvic inflammatory disease (PID)
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Hairy leukoplakia, oral
Herpes zoster (shingles), involving two or more episodes or at least one dermatome
Idiopathic thrombocytopenic purpura
Constitutional symptoms, such as fever (>38.5ºC) or diarrhea lasting >1 month
Peripheral neuropathy
Category C AIDS-Indicator Conditions
Bacterial pneumonia, recurrent (two or more episodes in 12 months)
Candidiasis of the bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical carcinoma, invasive, confirmed by biopsy
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month in duration)
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Cytomegalovirus disease (other than liver, spleen, or nodes)
Encephalopathy, HIV-related
Herpes simplex: chronic ulcers (>1 month in duration), or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1-month duration)
Kaposi sarcoma
Lymphoma, Burkitt, immunoblastic, or primary central nervous system
Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or
extrapulmonary
Mycobacterium tuberculosis, pulmonary or extrapulmonary
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)
Progressive multifocal leukoencephalopathy (PML)
Salmonella septicemia, recurrent (nontyphoid)
Toxoplasmosis of brain
Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight)
associated with either chronic diarrhea (two or more loose stools per day for ≥1 month) or
chronic weakness and documented fever for ≥1 month
Source: http://www.aidsetc.org/aidsetc?page=cg-205_hiv_classification
What are the clinical stages for HIV/ADIS?
Source: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf page 14
Details: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf page 17
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What are the available treatment options for people living with HIV/AIDS?
Anti-retroviral drugs (ART) are highly recommended for people infected with HIV and
those who have progressed to AIDS.
ART is recommended for all HIV-infected individuals. The strength of this recommendation
varies on the basis of pretreatment CD4 cell count:
o CD4 count <350 cells/mm3
o CD4 count 350 to 500 cells/mm3
o CD4 count >500 cells/mm3
Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the
following conditions:
o Pregnancy
o History of an AIDS-defining illness
o HIV-associated nephropathy (HIVAN)
o HIV/hepatitis B virus (HBV) co-infection
source: http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent●
treatment-guidelines/0/
What drugs are available?
There are 6 major classes of drugs used for HIV/AIDS treatment divided on basis of
their mechanism of action. More than 20 Anti-retroviral drugs have been approved for
treatment of HIV/AIDS. When several of these drugs, typically three or four, are taken in
combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART
and is found to be more effective.
The 6 classes include:
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fusion inhibitors (FIs) or entry inhibitors - interfere with the binding of the virus and
prevent its entry into the T-cell membrane, for example enfuvirtide;
CCR5 antagonists -bind to surface of T-cell and block viral attachment of the virus to the
cell, example Maraviroc,
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)- get incorporated into
newly synthesized viral DNA and inhibit reverse transcription,
non-nucleoside reverse transcriptase inhibitors (NNRTIs)- inhibit the enzyme reverse
transcriptase and act as a non-competitive inhibitor,
protease inhibitors (PIs)- inhibit the enzyme protease so viral assembly is affected ,
integrase strand transfer inhibitors (INSTIs) - inhibits the enzyme integrase which is
responsible for integration of viral DNA into DNA of infected cell.
http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/
11/what-to-start
*naïve patients are patients who have never taken the drug they are being administered
with before.
More Drug characteristics: http://aidsinfo.nih.gov/guidelines/html/1/adult-andadolescent-treatment-guidelines/35/appendix-b--drug-characteristic-tables
Drug prices: http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatmentguidelines/276/appendix-c--monthly-average-wholesale-price-of-antiretroviral-drugs
The complete list of FDA approved drugs for HIV/AIDS is available on
http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/
HIVandAIDSActivities/ucm118915.htm
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How are these drugs used?
Antiretroviral drugs reveal best results if they are used in combinations, as this also
avoids drug resistance. Usually a minimum of three drugs are combined from at least
two different drug classes. This is known as a regimen.
An initial ARV regimen generally consists of two NRTIs in combination with an NNRTI, a
PI (preferably boosted with ritonavir [RTV]), an INSTI (namely raltegravir [RAL]), or a
CCR5 antagonist (namely MVC).
More information about drug regimens: http://www.aidsinfo.nih.gov/Guidelines/HTML/
1/adult-and-adolescent-treatment-guidelines/11/what-to-start
An important HIV/AIDS information and treatment resource: http://aidsinfo.nih.gov/
ContentFiles/HIVandItsTreatment_cbrochure_en.pdf
Another resource: http://www.avert.org/
Sources for our information:
Pictures and Diagrams :
virus 1 image:
http://www.google.com/imgres?
q=Human+immunodeficiency+virus&hl=en&biw=1525&bih=743&tbm=isch&tbn
id=d9wwGSTjB1FldM:&imgrefurl=http://micro.magnet.fsu.edu/cells/viruses/
hivvirus.html&docid=2BBi42P5zHcUfM&imgurl=http://micro.magnet.fsu.edu/cells/viruses/images/
hivstructurefigure1.jpg&w=353&h=301&ei=nqmET_DNIsay0AGdj_2tBw&zoom=1&iact=hc&vpx=321&vp
y=224&dur=346&hovh=159&hovw=186&tx=117&ty=117&sig=106199872197656796846&page=1&tbnh
=159&tbn
w=186&start=0&ndsp=19&ved=1t:429,r:1,s:0,i:72
virus 2 image:
http://www.google.com/imgres?
hl=en&sa=X&biw=1366&bih=665&tbm=isch&prmd=imvnsfd&tbnid=Wj9aQER9
PXR4dM:&imgrefurl=http://www.labor-spiez.ch/en/the/bs/
enthebsvirwas.htm&docid=TcrV6M_Hbdc7MM&imgurl=http://www.labor-spiez.ch/images/the/ar/bs/
dethearbsvirwas02.gif&w=136&h=136&ei=eiagT8zgPKLv0gG0_MmAAg&zoom=1&iact=hc&vpx=954&vp
y=433&dur=414&hovh=108&hovw=108&tx=74&ty=74&sig=106199872197656796846&page=1&tbnh=1
08&tbnw=108&start=0&ndsp=19&ved=1t:429,r:17,s:0,i:107
lymphocyte image:
http://www.google.com/imgres?
q=types+of+leukocytes&hl=en&sa=X&biw=1525&bih=743&tbm=isch&tbnid=mK
mipmTR1eGKPM:&imgrefurl=http://www.lymphomation.org/aboutlay.htm&docid=jCoqDHBiipVd0M&imgurl=http://www.lymphomation.org/images/leukocytesnormal.gif&w=617&h=358&ei=9p5oT7DiDsbn0QGi95D7CA&zoom=1&iact=hc&vpx=161&vpy=298&dur=
2227&hovh=171&hovw=295&tx=172&ty=119&sig=105322174185390836594&page=1&tbnh=102&tbn
w=176&start=0&ndsp=32&ved=1t:429,r:8,s:0
HIV detailed picture:
http://health.howstuffworks.com/diseases-conditions/infectious/aids2.htm
Books Referenced:
Carter, John B., and Venetia A. Saunders. Virology: principles and applications.
Chichester, England: John Wiley & Sons, 2007. Print.
Clark, William R.. In defense of self: how the immune system really works. New York: Oxford
University Press, 2008. Print.
Crandall, Keith A.. The evolution of HIV. Baltimore, MD: Johns Hopkins University Press, 1999.
Print.
Dimmock, N. J., A. J. Easton, and Keith Leppard. Introduction to modern virology. 6th ed.
Malden, MA: Blackwell Pub., 2007. Print.
Levy, Jay A.. HIV and the pathogenesis of AIDS. 2nd ed. Washington, D.C.: ASM Press, 1998.
Print.
Norkin, Leonard C.. Virology: molecular biology and pathogenesis. Washington, DC:
ASM Press, 2010. Print.