Yoshimura: Basic Properties of HIV

Question 1

Lentivirus:

Answer 1

Lentivirus: cause disease that requires a long time to develop (usually takes ~10 years after infection with HIV to develop AIDS)

Question 2

Homology:

Most common form:

Answer 2

Types: share ~40% homology

HIV-I: most common form around the world

Question 3

HIV-II:

Answer 3

HIV-II: not as virulent and causes a disease that takes longer to develop and has a lower morbidity rate; common in West Africa

Question 4

Cellular Tropism

What is involved in the initial infection?

Answer 4

Monocyte/Dendritic Cell/Macrophage: involved in initial infection

Question 5

Cellular Tropism

What is involved in both initial and late infection?

Answer 5

CD4+ T Cells: involved in initial and late infection (depletion results in immunodeficiency)

Question 6

Cellular Tropism

What infection occurs in later stages?

Answer 6

Microglia: infection occurs at later stages and affects neurons indirectly; results in neurological disorders (HIV-associated dementia)

Question 7

3 Main Clinical Symptoms of AIDS:

Answer 7

CD4 T cell depletion

Neurological manifestations: 20-30% develop HAD

Neoplasms: Kaposi’s sarcoma, lymphoma (due to immunodeficiency)

Question 8

Transmission: (3)

Answer 8

Blood

Sexual transmission

Mother to infant (intrauterine or infection at birth; greatly decreased due to use of anti-retrovirals)

Question 9

Clinical Course of AIDS
Viremia

Where does HIV replication initially occur?
After this, where does it occur?
How do virus levels change?

Answer 9

HIV replication occurs initially in mononuclear cells (ie. dendritic cells) and a few CD4 T cells present at the site of entry

After this, replication predominantly in CD4 T cells

Initial spike in virus levels, followed by a decline during the persistent phase; levels will increase again during the development of AIDS

Question 10

Immune Response

Initial response:
Sustained period:

Answer 10

Initial response: result of initial increase in CD8 T cells

Sustained period: anti-gp120 Ab response; viremia kept in check during this time

Question 11

Immune Response

What is immunodeficiency the result of?
What happens soon after infection?

Answer 11

Immunodeficiency: result of depletion of CD4+ T cells

Soon after infection: some people develop an influenza or mononucleosis-like infection

Question 12

Persistent infection

What do cells infected with HIV contain?
What is produced in PBLs?

Answer 12

Cells infected with HIV contain proviral DNA integrated into their own DNA (doesn’t need to be expressed to be maintained by infected cell and passed onto progeny cells)

Only low amounts of virus produced in peripheral blood leukocytes (PBLs)

Question 13

Persistent infection

Where are high levels of virus produced?
How long can the persistent stage last?
May cause what?

Answer 13

High levels of virus produced in LNs

Persistent stage can last for years and can be asymptomatic

May cause peripheral generalized lymphadenopathy syndrome (PGL)

Question 14

AIDS:

CD4 count=

Answer 14

Eventually develop AIDS: wasting, opportunistic infections, neoplasms and CNS damage

When CD4 count is less than 200 cells/uL

Question 15

HIV Replication

Genome:

Answer 15

Complex Genome: multiple spliced messages

Question 16

HIV Replication

Adsorption and Entry:

Answer 16

Adsorption and Entry: binds both receptor and co-receptor

Question 17

HIV Replication

Receptor:
What binds the receptor?

Answer 17

Receptor: CD4

SU and the V3 bind CD4

Question 18

HIV Replication

What does SU bind?
What is SU composed of?
What is V3?

Answer 18

SU binds to the CD4 cellular receptor (gp120 kD for HIV)

SU: composed of both variable and constant regions of aa

V3: most important of these segments; immunodominant epitope recognized by neutralizing Abs (however, highly susceptible to mutation and therefore evades the immune response)

Question 19

HIV Replication

Co-receptors

Answer 19

Co-receptor: CCR5 (macrophage) and CXCR4 (T cells)

Question 20

HIV Replication

CCR5
Receptor type:
Present on:

Answer 20

CCR5: beta-chemokine receptor; present mainly on monocytes and a few CD4 T cells

Question 21

HIV Replication

CXCR4
Receptor type:
Present on:

Answer 21

CXCR4: alpha-chemokine receptor; present mainly on CD4 T cells

Question 22

What do “long-term progressers” have mutations in?

Answer 22

Important Point: “long-term progressers” (patients who are HIV positive but do not develop AIDS) are found to have mutations in either of these co-receptors (CCR5/CXCR4)

Question 23

Effects of mutations in CCR5 and CXCR4:

Answer 23

CCR5: overproduction of ligand, prevents HIV from binding (all spots take up by over produced ligand)

CXCR4: mutation to molecule prevents HIV binding

Question 24

HIV Replication
Basic Binding Process

What does CD4 bind?
Results in:
What releases the TM protein from the hydrophobic pocket?

Answer 24

CD4 binds the HIV gp120 molecule first

Results in conformational change so it can bind the co-receptor

Another conformational change occurs that releases the TM protein from the hydrophobic pocket, allowing it to attach to the cytoplasmic membrane

Question 25

Viral Proteins: (2)

Answer 25

Regulatory Proteins: essential for HIV replication Accessory Proteins: initially observed to be non-essential in vitro; may be important for pathogenesis in vivo

Question 26

Regulatory Proteins: (2)

Answer 26

Tat (transcriptional transactivator) | Rev (regulator of viral expression)

Question 27

Tat (transcriptional transactivator) Allows:

Answer 27

Transactivator of viral transcription allowing for high levels of viral RNA to be transcribed (without it, there would be very little transcription)

Question 28

Rev (regulator of viral expression) Regulates: What is unspliced RNA used for?

Answer 28

Regulates viral RNA transport of the following from the nucleus Unspliced RNA packaged into virions as genomic RNA (used for translation of Gag-Pol polypeptide precursor protein)

Question 29

Rev (regulator of viral expression) What is Single-spliced mRNA used for?

Answer 29

Single-spliced mRNA is used to encode envelope viral gp, which is an important component of infectious virus particles.

Question 30

Accessory Proteins: (4)

Answer 30

Nef (negative factor) Vpr (viral protein R) Vif (viral infectivity factor) Vpu (viral protein U)

Question 31

Accessory Proteins Nef (negative factor) Name: Downregulates: Prevents:

Answer 31

Nef (negative factor): name is a misnomer; predominantly cytoplasmic Downregulates CD4 and MHC class I: immune evasion Prevents apoptosis of infected cell

Question 32

Accessory Proteins Vpr (viral protein R) Role in ability to infect non-dividing cells: Arrests cellular proliferation:

Answer 32

Role in ability to infect non-dividing cells (ie. macrophages): disrupts nuclear membrane to allow transport of viral DNA into the nucleus Arrests cellular proliferation: cells accumulate in G2 phase of the cell cycle

Question 33

Accessory Proteins Vif (viral infectivity factor):

Answer 33

Inhibits cellular protein that normally degrades reverse transcribed viral DNA

Question 34

Accessory Proteins Vpu (viral protein U) Downregulates: Promotes virus budding via:

Answer 34

Downregulates CD4 expression: immune evasion Promotes virus budding: inhibition of cellular protein tetherin

Question 35

Highly Active Anti-Retroviral Therapy (HAART) | Examples: (2)

Answer 35

Highly Active Anti-Retroviral Therapy (HAART): combination drugs Examples: 2 nucleoside reverse transcriptase inhibitors (NRTIs) + 1 non-nucleoside RTI (NNRTI) 2 NRTIs + 1 protease inhibitor

Question 36

Vaginal gel containing RT inhibitor: Early HAART treatment: Pre-exposure prophylaxis (PrEP) for uninfected partner:

Answer 36

39-54% reduction in HIV infection 96% reduction in infecting partners 73% efficacy

Question 37

Vaccines: | New Treatments:

Answer 37

Vaccines: recombinant proteins - Production of neutralizing abs - Stimulation of CD8+ CTLs New Treatments: - RNA interference - Recombinant viral DNA