HIV infection:virology, pathogenesis and immunology

Question 1

What is HIV?

Answer 1

a retrovirus, an RNA virus which uses reverse transcriptase (RT) to make a DNA copy that becomes integrated into the DNA of the infected cell

Question 2

What are the 6 stages of virology?

Answer 2

1. Attachment
2. Cell entry
3. Interactions with host cells
4. replication
5. assembly
6. Release

Question 3

describe the first stage of virology- attachment

Answer 3

viral and cell receptors e.g. HIV

Question 4

describe the second stage of virology- cell entry

Answer 4

only central viral ‘core’ carrying the nucleic acid and some associated proteins enter host cell

Question 5

describe the third stage of virology- interaction with host cells

Answer 5

use cell materials (enzymes, amino acids, nucleotides) for their replication; subvert host cell defence mechanisms

Question 6

describe the fourth stage of virology- replication

Answer 6

may localize in nucleus in, in cytoplasm or at both; production of progeny viral nucleic acid and proteins

Question 7

describe the fifth stage of virology- assembly

Answer 7

occurs in nucleus, in cytoplasm or at cell membrane

Question 8

describe the sixth stage of virology- release

Answer 8

by bursting open of cell; or by exocytosis from the cell over a period of time

Question 9

what are the 9 stages of replication of HIV?

Answer 9

1.Attachment
2.Entry
3.Uncoating
4.Reverse transcription
5.Genome integration
6.Transcription of viral RNA
7.Splicing of mRNA and translation into proteins
8.Assembly of new virions
9.Budding

Question 10

which cells do HIV receptors infect

Answer 10

HIV infects cells that express CD4 and the interaction between CD4 and gp120 is conserved among all primate lentiviruses

Question 11

what induces a conformational change in gp 120

Answer 11

Binding of gp120 to CD4

Question 12

what does the co receptor binding site include

Answer 12

a conserved bridging sheet and also amino acids in the V3 loop

Question 13

how does HIV work

Answer 13

HIV fuses to CD4 receptor and passes its contents into CD4+ cell
It replicates in CD4 positive cell
The virus copies its RNA into DNA and used the host cell for gene transcription
It results in gradual damage to the immune system mainly through depletion of CD4 T-cells

Question 14

what are the co-receptors for the HIV replication cycle?

Answer 14

CCR5 and CXCR4

Question 15

what is the primary receptor for the HIV replication cycle?

Answer 15

CD4.

Question 16

what receptor is used in HIV-1 in early infection?

Answer 16

CCR5- may switch to use CXCR4 later in infection

Question 17

what does antiretroviral therapy target in the HIV replication cycle?

Answer 17

• integrase inhibitors
• protease inhibitors
• reverse transcriptase inhibitors
• fusion/ entry inhibitors

Question 18

can people with one copy of the mutant gene be infected?

Answer 18

can be infected with HIV but show delayed disease progression

Question 19

why can HIV-1 evolve rapidly?

Answer 19

1. Error-prone replication (the enzyme reverse transcriptase makes at least 1 error in every replication cycle)
2. Rapid viral replication (generation time ~2.5 days)
3. Large population sizes (~1010 new virus particles produced each day)

Question 20

how do HIV-1 clades ( groups)/ subtypes differ?

Answer 20

by >20% in amino acid sequence

Question 21

what increases HIV-1 diversity?

Answer 21

recombination between different clades/subtypes in the same person significantly increases HIV-1 diversity

Question 22

what are the symptoms of acute retroviral syndrome?

Answer 22

-“Glandular fever”-like illness
-Fever, lymphadenopathy
-Sore throat, oral ulcers
-Skin rash (upper trunk)
-May include neurological features

Question 23

what do immune responses during AHI ( acute HIV infection) determine?

Answer 23

Long-term viral control
Disease progression

Question 24

why is early initiation of antiretroviral therapy beneficial?

Answer 24

-Reduced risk of transmission
-Smaller reservoir, lower set-point, delayed progression

Question 25

what are the clinical features of untreated HIV-1 infection?

Answer 25

-Vaginal/oral candidiasis -skin disease -fatigue - bacterial pneumonia - herpes zoster - oral hairy leukoplakia, thrush, fever, diarrhoea, weight loss - kaposis sarcoma, non Hodgkins lymphoma - toxoplasmosis, oesophageal candidiasis, cryptococcosis - cns lymphoma - cmv, mycobacterium avum complex

Question 26

what are the key features of HIV pathogenesis?

Answer 26

1. HIV is integrated into the DNA of the infected CD4-expressing cells 2. HIV infects a range of CD4 + immune cells in addition to helper T-cells, (including regulatory T-cells, T follicular helper cells, dendritic cells, macrophages and thymocytes) 3. However, the number of HIV-infected CD4+ T-cells in the blood does not explain the extent of immune suppression 4. HIV can pass directly from cell to cell, and so it is relatively inaccessible to antibodies in the blood 5. The small HIV genome encodes a range of genes that enable the virus to evade human immune system responses

Question 27

Why does the immune response to HIV-1 fail to clear the virus?

Answer 27

1. One of the key immune responses to HIV-1, from CD4+ T-helper cells, is lost from very early in infection, because these are the cells HIV infects first 2. There is a very vigorous response from cytotoxic CD8+ T-cells, which provides the major force controlling viral replication but ultimately fail when “immune exhaustion” sets in

Question 28

what do CD8+ cytotoxic T cells do

Answer 28

identify cells expressing foreign material (from pathogens or tumours), processed as small fragments of protein (8-11 amino acids in length), presented on the surface of the infected cell by HLA class I molecules