Transcript Immune Reconstitution - UCLA Center for World Health

Immune reconstitution
Anjie Zhen, PhD
Overview of HIV life cycle
HIV life cycle:
1.
2.
3.
4.
5.
6.
7.
Binding and Fusion
Entry
Reverse transcription
Integration
Viral RNA and protein expression
Assembly and budding
Maturation
HIV target cells:
CD4T cells,
Macrohpages,
Dendritic cells
Anti-retroviral therapy
• HAART: Highly active anti-retroviral therapy
• Usually combine several drugs that target different stages of HIV
replication
• Classes:
– Entry inhibitors (Maraviroc/enfuvirtide)
– Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse
transcriptase inhibitors (NtRTI) (tenofovir, deoxythymidine, zidovudine, etc)
– Non-nucleoside reverse transcriptase inhibitors (NNRTI) (nevirapine, etc)
– Integrase inhibitors (Raltegravir)
– Protease inhibitors (Indinavir, Nelfinavir etc)
Overview of HIV life cycle
X
HIV life cycle:
1.
2.
3.
4.
5.
6.
7.
Binding and Fusion
Entry
Reverse transcription
Integration
Viral RNA and protein expression
Assembly and budding
Maturation
HIV target cells:
CD4T cells,
Macrohpages,
Dendritic cells
X
X
X
Effect of HAART in US
HIV disease progression –
clinical latency
Levels (Separate Scales)
Primary
infection
Acute
Asymptomatic
(clinical latency)
CD8+ T cell
AIDS and
Death
HIV viral load
Neutralizing Antibodies
CD4+ T cell
4–8
weeks
Years
T cell homeostasis
Immune reconstitution during HAART
– Phase 1: Sudden halt in viral production provokes a rapid increase
in CD4 T cells in the first three months
– Phase 2: Slow recovery over several years, results mostly from
regeneration of naïve CD4 T cells population.
Immune reconstitution during HAART
– Restoration of pathogen and HIV-specific T
lymphocytes
HAART effects on immune
response
– Increase CD4 cell number and function
– Increase memory and naïve CD4 and CD8 cells
– Decrease markers of cellular activation
– Normalize distortion in CD4 repertoire
– Reconstitution of antigen-specific CD8 T cell
and B cell responses to opportunistic
pathogens
Viral Latency
•The latent viral pool persists in everyone following Highly Active
Anti-Retroviral Therapy (HAART)
•Is established soon after infection
•T1/2 of replication competent virus is ~44 months therefore
eradication could take up to 60 years.
Evidence of Viral Reservoirs
Plasma Viral RNA
Primary Infection
Viral Rebound
Viral Setpoint
Cessation
Of HAART
HAART
50
copies
Infection
Model for establishment and maintenance of HIV-1
reservoirs
Death
Activation:
antigen
Activated T-cell
Quiescent T-cell
Activated T-cell
and renewed
viral replication
HIV T cell dynamic on and off HAART
Factors influencing immune restoration with
antiretroviral therapies
Blood, 2011
Therapeutic possibilities to improve immune
reconstitution
Targeting HIV latent reservoir
Q&A
What is HAART?
Can virus be cleared by HAART and why?
What are the two phase of immune reconstitution after initiation of antiretroviral therapy?
Q&A
What is HAART?
HAART stands for Highly Active Antiretroviral Therapy. The usual HAART
regiment combines three or more different drugs.
Can virus be cleared by HAART and why?
HAART regiments can reduce the amount of active virus and in some case can
lower the number of virus until it is undetectable by current blood testing
techniques. However, usual HAART treatment cannot clear HIV infection due to
the fact that virus can establish latent infection in the patient.
What are the two phase of immune reconstitution after initiation of antiretroviral therapy?
First a rapid initial rise of CD4 T cell counts in the first few months, primarily due
to increase in memory T cells, and followed by a slow, steady increase in naïve T
cell counts that can continue for years with sustained suppressive ART.
Strategies targeting latent reservoirs
How to reactivate latently infected cells?
How to improve immune responses to eliminate infected cells?
Kick and kill
R
T
HAART
R
T
Activators
R
T
R
T
Kill
Active infection
Latency
Enhanced CTLs
Via engineered
Immunity
Broad neutralizing
antibodies