Lecture 75 - HIV Biology

Question 1

HIV Taxonomy-- 
Family
subfamily 
genus 
species

Answer 1

○ Family: Retroviridae
○ SubFamily: Orthoretrovirinae

○ Genus: Lenti-virus

○ Species: RetroVirsues

Question 2

What are some features of all retroviruses? all lenitviruses

Answer 2

• Retrovirus: RNA genome, RT, integrate (provirus), Accessory Genes (Gag, Pol, Env); tRNA Lysine
• Lentivirus: “Slow” = long incubation period

Question 3

HIV morphology and structure:

Answer 3

Enveloped -
Env GlycoProteins – Gp120, Gp41

The Matrixx: Gag p17

The Capsid: gag p24 – bullet shaped;

Question 4

What proteins are encoded for by Env, Gag, Pol?

What are their functions ?

Answer 4

Env:
gp120 - Docking protein; makes first contact with CD4s
gp41 - Transmembrane protein impt for fusion and entry

Gag
p17 - The Matrix
p24 – the Capsid
p7 - nucleocapsid

Pol – RT, integrase, protease

Question 5

What is in the HIV capsid?

Answer 5

2 copies of viral RNA

RT

Inegrase

p7 nucleocapsid

Lysine tRNA

Question 6

what proteins are the main targets for vaccine efforts?

what the limitations to development?

Answer 6

env gp120, gp41

rapid mutations
Envelope is heavily glycosylated – hard for Ab to access epitope
different groups and clades
Integrates into genome and undergoes latency

Question 7

What are the modes of Transmission for HIV ?

what three ways can HIV enter mucosally?

Answer 7

Parenteral – IV injection, skin infection, IM infejection

Mucosal – sexual contact; mother to child

Mucosal Entry –
Dendritic cells
Breach of the epithelail layer
Transcytosis

Question 8

Describe the HIV Lifecycle in brief

Answer 8

gp120 Attachment of the Virus with CCR5 or CXCR5

Fusion -gp 41
Uncoating the capsid

TR of RNA into dsDNA

Nuclear entry and integration (integrase)

Synthesis of viral RNA – viral proteins — budding release

Question 9

Describe the CCR5 Mutation that allows for different progression of disease

Answer 9

CCR5 delta 32

Heterozyogous – 18% of caucausians; can contract the disease but progress to HIV very slowly

Homozygous – 1% of caucasians
Highly resistant to infection
still susceptible to CXCR4 mediated disease

Question 10

Describe how HIV gains entry into a host cell?

Describe the tropism of the chemokine receptors?

Answer 10

GP120 interacts with CD4 co-receptor and undergoes a conformational change allowing it to interact with CCR5 or CXCR4

GP41 – fusion peptide inserts into the membrane of the host cell

• CCR5: macrophages and T cells (infections here present throughout)

CXCR4: T cells and primary CD4 T cells (infections here present only in late stages)

Question 11

What drugs block interactions between HIV glycoproteins and host cell receptors?

Answer 11

Maraviroc – blocks interaction of GP120 and co-receptor CCR5

Enfuvirtide — blocks GP 41 from interation with Target cell

Question 12

Describe the function of RT?what primer is necessary?

What drugs block RT?

Answer 12

– RNA –> dsDNA

Needs tRNA: lysine

Nuceloside analogs, nucelotide analogs, nonnucleoside analogs

Question 13

Name the Structural Genes, the Transactivator genes, and the accessory genes

Answer 13

Structural: gag, pol, env

Transactivator: tat and rev

Accessory: Nef, Vif, Vpu, and Vpr

Question 14

Describe the Transcription of the integrated HIV Provirus?

• important Tx factors
• significance of multiply spliced genome ?
• whats in the u3 region?
• whats in the R region

Answer 14

Impt Tx Factors: Sp1, AP1 and NfKB

Multiply spliced genome: overall HIV genome is small; multiply splicing allows for different gene products to be spliced together? allowing for more proteins to be synthesized from 1 segment?

U3 Region – regulatory elements

R region - TAR stem loop

Question 15

Describe the Function of TAT ?

Answer 15

TAT – Booster of HIV transcription

• binds TAR (R loop; 5’ LTR);
• Recruits PTEfb (cdk9 + CycT)
• Phosphorylation
• turns on RNA Pol II

Question 16

Describe the function of REV

Answer 16

• made in the cytosol, moves the nucleus;
• binds transcripts with RRE
• Forms complex with XPO and ranGTP
• helps migrate transcripts out of the nucleus for translation

Question 17

Functions of Accessory Proteins: NEF,

Answer 17

NEF - only found in primary lentivirus;

• Downregulates CD4 - allowing for more efficient release of the virus
• Downregulates MHC Class 1 -
• Downregulates CD28 – allows virus to achieve latency

Question 18

Function of Accessory protein: VPU and VIF

Answer 18

VPU – expressed late; CD4 Downregulatiion
Antagonizes BST/Tetherin (integral membrane protein that hinders viral release)

VIF – Targets APOBEC3G for degradation; preventing ongoing hypermutations which could be inactivating

Question 19

How Does HIV Kill cells ?

Answer 19

Direct Killing – induces cell death

Apoptosis - upregulates fasL in infected cells; kills neighboring cells with Fas

Misdirect ADCC responses –

Misdirects CTL responses

Question 20

Describe the Acute vs Chronic phases of HIV?

Answer 20

Acute – initial viremia shortly after infection.

Latency (chronic) – CTLs and then neutralizing control the viremia at a set point (which can last years)

However CD4s are falling gradually

Mutations to gp120 may help HIV escape from neutralization

Inflection point – rapid rise in viremia; fall in CD4s leading to OIs and AIDS

T cell crash