Lecture 14 - HIV Natural History, Antiretroviral Therapy

Question 1

Time after infection that HIV enters acute HIV syndrome phase

Answer 1

~3 weeks

Question 2

Time after infection that HIV enters latent phase

Answer 2

~9 weeks

Question 3

HIV RNA copies in plasma during latent phase

Answer 3

10^3 - 10^4 copies/mm^3 plasma

Question 4

Does viral replication decrease to reach setpoint?

Answer 4

No.

Viral replication is the same (~10 billion/day), but immune system is controlling virus

Question 5

Normal [CD4+]

Answer 5

500-900cells/mm^3

Question 6

Diseases present in advanced AIDS

Answer 6

Strange infections, malignancies that aren’t present in immunocompetent people.

EG: PCP, Kaposi’s sarcoma

Question 7

Diseases characterising intermediate HIV infection

Answer 7

Autoimmune disorders

Not uncommon enough to point to HIV infection

Question 8

Definition of AIDS

Answer 8

[CD4+]<200 cells/mm^3 plasma, one or more opportunistic infections or unusual malignancies

Question 9

Important transmissible disease in HIV+

Answer 9

Tuberculosis

Question 10

T lymphocyte homeostasis
1)
2)
3)

Answer 10

1) Naive T cells undergoing homeostatic proliferation
2) On contact with antigen, some become memory, some effector
3) Central memory cells upon contact with antigen become effectors

Question 11

Causes of HIV T cell decline
1)
a, b, c, d, e
2) 
a, b

Answer 11

1) Increased destruction of T cells
a) Lysis
b) Incomplete reverse transcription in naive cells can lead to apoptosis
c) Syncitium formation
d) Immune activation
e) Lymph node fibrosis

2) Defective production of T cells
a) Thymus impairment
b) CD34+ progenitor destruction

Question 12

Syncitium

Answer 12

Uninfected cells cluster around infected cells (gp120 displayed on infected cell surface)

Question 13

Reasons for CD4+ depletion variability between patients
1) 
a, b, c
2) 
a, b, c

Answer 13

1) Viral factors
a) X4 virus leads to greater CD4+ loss
b) nef deleted virus leads to lesser T cell loss
c) CMV, GBV-C infections

2) Host factors
a) HLA type
b) CCR5 mutations - delta32 slows disease progression
c) Age

Question 14

Why is age a factor in CD4+ loss rate?

Answer 14

Thymus function impaired at very young and very old ages

Question 15

Why is HLA type a determinant of CD4+ loss rate?

Answer 15

Different MHC molecules are more effective at presenting HIV epitopes

Question 16

CD8+ immunopathology in HIV

Answer 16

Abnormally high numbers in acute phase

Numbers decline at later stages of disease

Question 17

NK cell immunopathology in HIV

Answer 17

Impaired numbers, impaired function

Question 18

Monocyte/macrophage immunopathology in HIV
1)
2)
3)

Answer 18

1) Defective chemotaxis
2) Defective Fc receptor function
3) Can’t initiate T cell proliferation

Question 19

B cell immunopathology in HIV
1)
2)

Answer 19

1) Produce more IgG and IgA

2) Decrease in antibody responses

Question 20

Effect of HIV on the immune system
1)
2)

Answer 20

1) Depletes CD4+ T cells

2) Chronic immune activation

Question 21

Reasons for HIV-induced chronic immune activation
1)
2)
3)
4)

Answer 21

1) Mucosal depletion of CD4+ T cells
2) Activation of innate immune systems
3) Anti-CMV responses
4) Loss of Treg cells

Question 22

Why does depletion of mucosal CD4+ lead to chronic immune activation?
1)
2)

Answer 22

1) Increased microbial translocation across mucosal surfaces

2) Increased activation of TLR4, TLR5, etc

Question 23

Why are innate immune systems activated in HIV infection?
1)
2)
3)

Answer 23

1) HIV RNA is a TLR7/8 ligand
2) Increased plasma TNFa
3) Greater bacterial invasion of GIT

Question 24

pDC

Answer 24

Plasmacytoid dendritic cells

Found mostly in peripheral lymphoid organs

Question 25

Why is there a greater CMV-specific response in HIV infection?
1)
2)

Answer 25

1) CMV no longer in latent state, begins to proliferate

2) Expansion of anti-CMV CD4 and CD8

Question 26

Factors released by chronically-activated immune system in HIV infection
1)
2)
3)
4)
5)

Answer 26

1) TNFa
2) IL-6
3) IL-10
4) CXCL-10
5) IFNa

Question 27

Two contrasting animal models for HIV

Answer 27

1) Sooty mangabey - Healthy

2) Rhesus macaque - AIDS-like symptoms

Question 28

Do sooty mangabeys experience a large proliferation of SIV particles in infection?

Answer 28

Yes

Despite this, don’t develop AIDS, no CD4 depletion

Question 29

cART

Answer 29

Combination antiretroviral therapy

Question 30

NRTIs/NNRTIs

Answer 30

Nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Question 31

Types of drugs involved in cART
1)
2)
3)
4)
5)

Answer 31

1) CCR5 antagonists
2) Fusion inhibitors
3) Integration inhibitors
4) Non-/Nucleoside reverse transcriptase inhibitors
5) Protease inhibitors

Question 32

Number of people in low- and middle-income countries now on HART

Answer 32

10 million

Question 33

Effects of beginning cART

Answer 33

[HIV] in blood drops to undetectable levels in between 1-3 months
CD4+ T cell levels recover after several months

Question 34

Strong determinant of life span on HART

Answer 34

How soon after infection HART begins, how much CD4+ levels have dropped by the time treatment begins

Question 35

Number of people worldwide estimated to know of their HIV infection

Answer 35

~50%

Question 36

Number of HIV+ in Australia receiving treatment

Answer 36

80%

Question 37

Current causes of deaths in HIV+
1)
2)

Answer 37

1) Decline in AIDS deaths

2) Non-AIDS deaths remain constant

Question 38

Non-AIDS deaths
1)
2)
3)
4)
5)
6)

Answer 38

1) Myocardial infarctions
2) Non-AIDS malignancy
3) Liver disease
4) Bone disease
5) Kidney disease
6) Bone disorders

Question 39

Why might non-AIDS deaths occur at a greater rate in HIV+?
1)
2)
3)

Answer 39

Combination of:

1) Virus still present at low levels
2) Immune dysfunction
3) cART toxicity

These lead to a premature-ageing phenotype

Question 40

How long on HART does it take for CD4 count to return to normal

Answer 40

On average 7 years

Question 41

Similar condition to HIV patients on HART

Answer 41

Ageing