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Immune reconstitution
Anjie Zhen, PhD
Overview of HIV life cycle
HIV life cycle: 1.Binding and Fusion2.Entry3.Reverse transcription4.Integration5.Viral RNA and protein expression6.Assembly and budding7.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
HIV life cycle: 1.Binding and Fusion2.Entry3.Reverse transcription4.Integration5.Viral RNA and protein expression6.Assembly and budding7.Maturation
HIV target cells:CD4T cells, Macrohpages, Dendritic cells
X
X
X
X
Effect of HAART in US
HIV disease progression – clinical
latency
Levels
(S
ep
ara
te S
cale
s)
CD4+ T cell
HIV viral loadCD8+ T cell
Neutralizing Antibodies
Years
AIDS and DeathAcute Asymptomatic
(clinical latency)
4 – 8 weeks
Primary infection
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 ActiveAnti-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
Infection
Primary Infection
Viral Setpoint
HAART
CessationOf HAART
Pla
sma
Vira
l RN
A Viral Rebound
50 copies
Model for establishment and maintenance of HIV-1 reservoirs
Activated T-cell
Death
Quiescent T-cell
Activation: antigen
Activated T-celland renewedviral 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 anti-retroviral 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 anti-retroviral 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?