Lecture 14 - HIV Natural History, Antiretroviral Therapy Flashcards Preview

Molecule to Malady > Lecture 14 - HIV Natural History, Antiretroviral Therapy > Flashcards

Flashcards in Lecture 14 - HIV Natural History, Antiretroviral Therapy Deck (41):
1

Time after infection that HIV enters acute HIV syndrome phase

~3 weeks

2

Time after infection that HIV enters latent phase

~9 weeks

3

HIV RNA copies in plasma during latent phase

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

4

Does viral replication decrease to reach setpoint?

No.
Viral replication is the same (~10 billion/day), but immune system is controlling virus

5

Normal [CD4+]

500-900cells/mm^3

6

Diseases present in advanced AIDS

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

EG: PCP, Kaposi's sarcoma

7

Diseases characterising intermediate HIV infection

Autoimmune disorders
Not uncommon enough to point to HIV infection

8

Definition of AIDS

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

9

Important transmissible disease in HIV+

Tuberculosis

10

T lymphocyte homeostasis
1)
2)
3)

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

11

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

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

12

Syncitium

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

13

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

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

14

Why is age a factor in CD4+ loss rate?

Thymus function impaired at very young and very old ages

15

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

Different MHC molecules are more effective at presenting HIV epitopes

16

CD8+ immunopathology in HIV

Abnormally high numbers in acute phase
Numbers decline at later stages of disease

17

NK cell immunopathology in HIV

Impaired numbers, impaired function

18

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

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

19

B cell immunopathology in HIV
1)
2)

1) Produce more IgG and IgA
2) Decrease in antibody responses

20

Effect of HIV on the immune system
1)
2)

1) Depletes CD4+ T cells
2) Chronic immune activation

21

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

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

22

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

1) Increased microbial translocation across mucosal surfaces
2) Increased activation of TLR4, TLR5, etc

23

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

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

24

pDC

Plasmacytoid dendritic cells
Found mostly in peripheral lymphoid organs

25

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

1) CMV no longer in latent state, begins to proliferate
2) Expansion of anti-CMV CD4 and CD8

26

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

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

27

Two contrasting animal models for HIV

1) Sooty mangabey - Healthy
2) Rhesus macaque - AIDS-like symptoms

28

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

Yes
Despite this, don't develop AIDS, no CD4 depletion

29

cART

Combination antiretroviral therapy

30

NRTIs/NNRTIs

Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors

31

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

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

32

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

10 million

33

Effects of beginning cART

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

34

Strong determinant of life span on HART

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

35

Number of people worldwide estimated to know of their HIV infection

~50%

36

Number of HIV+ in Australia receiving treatment

80%

37

Current causes of deaths in HIV+
1)
2)

1) Decline in AIDS deaths
2) Non-AIDS deaths remain constant

38

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

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

39

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

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

These lead to a premature-ageing phenotype

40

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

On average 7 years

41

Similar condition to HIV patients on HART

Ageing