Lecture 14 - HIV Natural History, Antiretroviral Therapy Flashcards
Time after infection that HIV enters acute HIV syndrome phase
~3 weeks
Time after infection that HIV enters latent phase
~9 weeks
HIV RNA copies in plasma during latent phase
10^3 - 10^4 copies/mm^3 plasma
Does viral replication decrease to reach setpoint?
No.
Viral replication is the same (~10 billion/day), but immune system is controlling virus
Normal [CD4+]
500-900cells/mm^3
Diseases present in advanced AIDS
Strange infections, malignancies that aren’t present in immunocompetent people.
EG: PCP, Kaposi’s sarcoma
Diseases characterising intermediate HIV infection
Autoimmune disorders
Not uncommon enough to point to HIV infection
Definition of AIDS
[CD4+]<200 cells/mm^3 plasma, one or more opportunistic infections or unusual malignancies
Important transmissible disease in HIV+
Tuberculosis
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
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
Syncitium
Uninfected cells cluster around infected cells (gp120 displayed on infected cell surface)
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
Why is age a factor in CD4+ loss rate?
Thymus function impaired at very young and very old ages
Why is HLA type a determinant of CD4+ loss rate?
Different MHC molecules are more effective at presenting HIV epitopes
CD8+ immunopathology in HIV
Abnormally high numbers in acute phase
Numbers decline at later stages of disease
NK cell immunopathology in HIV
Impaired numbers, impaired function
Monocyte/macrophage immunopathology in HIV
1)
2)
3)
1) Defective chemotaxis
2) Defective Fc receptor function
3) Can’t initiate T cell proliferation
B cell immunopathology in HIV
1)
2)
1) Produce more IgG and IgA
2) Decrease in antibody responses
Effect of HIV on the immune system
1)
2)
1) Depletes CD4+ T cells
2) Chronic immune activation
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
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
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
pDC
Plasmacytoid dendritic cells
Found mostly in peripheral lymphoid organs
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
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
Two contrasting animal models for HIV
1) Sooty mangabey - Healthy
2) Rhesus macaque - AIDS-like symptoms
Do sooty mangabeys experience a large proliferation of SIV particles in infection?
Yes
Despite this, don’t develop AIDS, no CD4 depletion
cART
Combination antiretroviral therapy
NRTIs/NNRTIs
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
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
Number of people in low- and middle-income countries now on HART
10 million
Effects of beginning cART
[HIV] in blood drops to undetectable levels in between 1-3 months
CD4+ T cell levels recover after several months
Strong determinant of life span on HART
How soon after infection HART begins, how much CD4+ levels have dropped by the time treatment begins
Number of people worldwide estimated to know of their HIV infection
~50%
Number of HIV+ in Australia receiving treatment
80%
Current causes of deaths in HIV+
1)
2)
1) Decline in AIDS deaths
2) Non-AIDS deaths remain constant
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
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
How long on HART does it take for CD4 count to return to normal
On average 7 years
Similar condition to HIV patients on HART
Ageing
