03/09d Retroviruses II

Question 1

What’s in the HIV virion?

Answer 1

Transmembrane glycoproteins - necessary for attachment
Protease, integrase, and reverse transcriptase - necessary for viral replication
Gag - necessary for assembly and packaging of the virion

Question 2

How does HIV attach to cells to initiate a round of replication?

Answer 2

CD4 is the primary receptor
CXCR4 and CCR5 are chemokine co-receptors
Primary tropism is CCR5; shifts to CXCR4 later in infection

Question 3

What are the three steps of HIV entry into host cells?

Answer 3

1) HIV binds to CD4 - induces a conformational change in gp120
2) Conformational change allows binding to the chemokine co-receptor, which exposes gp41 (involved in fusion)
3) HIV envelope fuses with the host cell membrane

Question 4

What are HDFs?

Answer 4

HIV-dependency factors - host proteins that HIV depends on for survival (LOTS of them)

Question 5

What are some natural host inhibitors of HIV attachment?

Answer 5

Beta chemokines
SDF-1 blocks CXCR4-mediated attachment
RANTES, MIP1-alpha, and MIP1-beta block CCR5-mediated attachment

Question 6

How do HIV fusion inhibitors like Fuzeon work?

Answer 6

Inhibit the high-energy coiled-coil structure that is necessary for viral fusion with the host cell membrane

Question 7

How does Miraviroc work?

Answer 7

CCR5 inhibitor

Only effective against CCR5-tropic viruses

Question 8

At what stages of the HIV life cycle are there FDA-approved medications to prevent HIV infection?

Answer 8

Viral fusion
Co-receptor binding (CCR5)
Reverse transcription from RNA to cDNA
Integration into the host genome
Protease cleavage and maturation

Question 9

How do the approved reverse transcriptase inhibitors work?

Answer 9

Nucleoside RT inhibitor - binds to the nascent cDNA chain and terminates its production
Non-nucleoside RT inhibitor - binds to RT and denatures it so that it cannot produce cDNA

Question 10

How do the approved integrase inhibitors work?

Answer 10

Prevent the 3` end processing and strand transfer reactions that are necessary to integrate HIV cDNA into the host genome

Question 11

How do the approved protease inhibitors work?

Answer 11

Active late in the virus life cycle
Interfere with virion assembly and maturation at the cell surface - bind to the HIV protease active site
Without protease, viral particles are produced but they are non-infectious

Question 12

What are the difficulties with developing therapeutic interventions?

Answer 12

Emergence of drug-resistant viruses
Reservoirs of virus - latently infected cells
Toxicity, dose, and expense of the drug itself
Patient non-compliance

Question 13

In 2009 it was reported that a patient was “cured” of HIV - how was this achieved?

Answer 13

Via a bone marrow transplant with CCR5-delta-32 stem cells

Question 14

What is the eclipse phase?

Answer 14

Phase during HIV infection when virus has infected the cell, but there is no antibody response yet
Viral infection may not be detected at this point unless you use PCR

Question 15

Why is CD4 T cell activation a “double-edged sword”?

Answer 15

CD4 T cells help antiviral responses, but activated cells provide more targets for viral replication

Question 16

What population of T cells is rapidly and irreversibly depleted during acute HIV infection? Why is this important?

Answer 16

Mucosal CD4+ T cells, found in gut-associated lymphoid tissue (GALT)
This depletion precedes depletion of the same cells in the blood and lymph nodes
New therapies should be directed to prevent this?

Question 17

What other cell types besides CD4 T cells play a role in HIV infection?

Answer 17

Macrophages
Dendritic cells
Langerhans cells

Question 18

What are the three dominant mechanisms for CD4 T cell loss in HIV infection?

Answer 18

1) Direct viral killing of infected cells
2) Increased susceptibility to apoptosis of uninfected cells, due to upregulation of and interaction with Fas in infected cells
3) Killing of infected cells by specific cytotoxic CD8 cells

Question 19

Variation in what genes has been associated changes in the progression of HIV infection?

Answer 19

Chemokines and cytokines such as CCR5 and SDF-1

HLA alleles

Question 20

What is APOBEC?

Answer 20

Innate mechanism for resisting HIV infection

Deaminates cytosine residues in nascent retroviral cDNA

Question 21

How does HIV deal with APOBEC?

Answer 21

Encodes the protein Vif, which mediates APOBEC degradation

Question 22

What is TRIM5-alpha?

Answer 22

Protective mechanism against retroviral infection
Blocks protein uncoating of the virus in the cell
Found in many mammals, and is responsible for species-specific infection by HIV and SIV

Question 23

What is tetherin?

Answer 23

Innate mechanism for resisting HIV infection

“Tethers” HIV to the surface of the host cell, preventing it from budding and maturing

Question 24

How can we control HIV infection?

Answer 24

1) Prevent virus infection and/or replication
2) Eliminate HIV reservoirs, such as latently infected cells
3) Restore immunity

Question 25

What would an HIV vaccine require in order to be effective?

Answer 25

Early induction of persistent inhibitory antibodies that can act immediately at the time of HIV transmission
Induction of broadly cross-reactive cytotoxic T cells
Induction of mucosal immunity

Question 26

How is HIV NOT acquired?

Answer 26

Casual contact
Food and drink
Inhalation
Saliva
Tears
Perspiration
Insect bites

Question 27

What are some recent major avenues of HIV prevention (besides safe sex!)?

Answer 27

Preventing mother-to-child transmission by treating both mother and child around the time of birth
Circumcision
Female microbicide
Oral Truvada - prophylactic for MSM
RV144 vaccine trial