Immune reconstitution Anjie Zhen, PhD. Overview of HIV life cycle HIV life cycle: 1.Binding and...

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?