Download Lecture 12: HIV Infection

Lecture 12: HIV Infection
Questions to Consider
 How does HIV-1 use the efficiency of the immune system to
efficiently infect and destroy the immune system?
 What features of HIV-1 replication permit it to evade the
immune system as well as to become resistant to
antiretrovirals?
 How is HIV-1 replication regulated to synchronize its
replication to that of its host cell?
 What molecular mechanisms are used by HIV-1 to evade
innate anti-viral cellular responses?
Mode of HIV Transmission
Flint, Principles of Virology, 2nd Ed.
Infectivity of Body Fluids and Cells
Flint, Principles of Virology, 2nd Ed.
Initiation of HIV-1 Infection
Initiation of HIV-1 Infection
Abbas- Cellular and Molecular Immunology
M Cells May Provide a Portal for HIV-1 Entry
Rapid Depletion of Intestinal CD4+ T
Cells After HIV Infection
JEM,
2004;200:6:749
HIV Uses the Mucosal Immune System to Disseminate
Overview of the Course of HIV-1 Infection
Abbas- Cellular and Molecular Immunology
Clinical Course of HIV-1 Infection Is Associated
With Depletion of CD4+ T Cells
Course of HIV Infection and Onset of
Immunodeficiency
Flint, Principles of Virology, 2nd Ed.
HIV Infection Causes Destruction of
Lymphoid Tissue Architecture
Flint, Principles of Virology, 2nd Ed.
HIV Infection Causes Destruction of
Lymphoid Tissue Architecture
Flint, Principles of Virology, 2nd Ed.
Structure of HIV-1
The HIV-1 Genome Encodes Structural
and Regulatory Proteins
HIV Transcription Involves Multiple
Reading Frames and RNA Splicing
HIV-1 Entry, Transcription and Integration
Entry of HIV-1 Requires Interaction of gp120
With CD4 and a Chemokine Receptor
Abbas- Cellular and Molecular Immunology
Divergent Behavior of HIV Isolates:
M-tropic and T-tropic Isolates
 M-tropic HIV isolates infect monocytes, primary T
lymphocytes and NOT T cell lines.
 M-tropic isolates initiate infection after transmission
and are the predominant isolate until late in the
disease course.
 T-tropic HIV isolates infect, T cell lines, primary T
lymphocytes and NOT monocytes
 T-tropic isolates are the predominant isolate in later
stages of the disease course.
M-tropic and T-tropic HIV Isolates are
Defined by Their Use of Coreceptors
Flint, Principles of Virology, 2nd Ed.
A Broad Range of Chemokines Selectively Induce the
Migration of Different Inflammatory Cells
CXC Motif Chemokines
CC Motif Chemokines
Reverse Transcription is Critical for Translation
of HIV-1 RNA Genome Into DNA
Activated T Cells are The Primary Source of HIV-1
but Memory Cells are the Primary Reservoir
Abbas- Cellular and Molecular Immunology
Rapid Kinetics of HIV-1 Replication and High Error Rate
of RT Contribute to the Emergence of Mutants
 Rapid HIV-1 infectious cycle-
~109 HIV particles produced daily.
 HIV-1 life span
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
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free virions- 8 hrs
 HIV-1-infected cells- 2.2 days
~ 300 replication cycles/year
Because RT does not proof-read,
one mutation/104 bases occurs.
With a genome of 104 bases, a
mutation occurs at each position
HIV-1 over 10,000 times every day.
This generates resistant mutants
that will selectively become the
predominant population.
Rapid Emergence of HIV-1 Drug Resistant Mutants
Immune Response Directed Against HIV-1
Controls but Does Not Eradicate Infection
The CTL Response is Critical to Control
Viral Infections
There Are Two Different Types of MHC Molecules
Capable of Presenting Peptides to T Cells
Virally Encoded Proteins Are Presented by
MHC Class I Molecules
Presentation of Peptide to CD8 by
Class I MHC Molecules
T cell epitopes
Peptide
MHC
Class I
From Dr. Stanley
Nathenson
Anchor Residues
Possible Strategies Used by HIV to
Evade the CTL Response
 Generation of immune epitope escape mutants
 Reduction in the level of HLA class I molecule
surface expression
 Decreasing the qualitative activity of HIV-specific
CTLs
 suppressing their function by chronic antigenic
exposure
 decreasing their perforin production
 shortening their telomere length
 increasing their susceptibility to apoptotic death.
 Reduction in available CD4+ T lymphocyte help
Anchor Residue Motifs Determine Binding of
Peptides to MHC Molecules
HIV Mutates Anchor Residue of Immunogenic
Epitope to Evade CTL Response
Nature 2001;412:334
HIV Mutates Anchor Residue of Immunogenic
Epitope to Evade CTL Response
Nature 2001;412:334
Nef Downregulates Surface Expression
of CD4 and MHC Class I Molecules
Flint, Principles of Virology, 2nd Ed.
Nef Downregulates MHC Class I Expression
Protecting HIV-infected Cells From CTLs
Nature. 1998;391:397
HIV-specific CTL Immunity May Be Compromised by
Expression of Immunoinhibitory PD-1
J Exp Med. 2006;203:2223.
Using Lentiviral Vectors To Reprogram CD8
CTLs To Be HIV-specific
Neutralizing Antibodies Can
Prevent Viral Infection
Differential Effect of Antibodies on
HIV Infection
Flint, Principles of Virology, 2nd Ed.
Neutralizing Antibodies Bind Sites on gp41
Nabel, Science 308 (5730), 1878.
Neutralizing Antibodies Bind Sites on gp120
Nature Immunology 5, 233 - 236 (2004)
Escape of HIV From Passsive anti-HIV
Antibody Therapy (2F5, 4E10, 2G12)
Nature Medicine 2005;11:593
The Capacity of Each Antibody to Recognize HIV is
Conferred by a Small Highly Unique Region Generated
by Genetic Shuffling
Using Gene Therapy To Educate B Cells to Make
Broadly Neutralizing HIV-specific Antibodies
Clone out the antiHIV antibody genes
into a lentivector
B cell making neutralizing
Antibodies to HIV
Genetically educated B cell from an
HIV-infected patient now makes
broadly neutralizing antibodies
to HIV
Uneducated B cell from an
HIV-infected patient
Lentivirus
antibody gene
therapy vector
Activated T Cells are The Primary Source of HIV-1
but Memory Cells are the Primary Reservoir
Abbas- Cellular and Molecular Immunology
Differential HIV-1 Replication Rates in Different Cells
Can Result in Latent Infection or Lysis
Scientific American October 1988
TCR Signal Transduction Uses Nuclear Binding
Proteins
Abbas- Cellular and Molecular Immunology
HIV-1 LTR is Regulated by
Cellular Nuclear Binding Proteins
The HIV-1 Proteins Tat and Rev are Critical for
HIV-1 Virion Production
Secondary Structure of TAR and Rev-Responsive
Element (RRE)
HIV Transcription Involves Multiple
Reading Frames and RNA Splicing
Rev Protein is Required for
Transport of Unspliced HIV mRNA
Rev Protein is Required for Transport of
Unspliced HIV-1 Structural RNAs
CRS- cis restrictive sequence
CAR- cis acting region
No Rev
+ Rev
Scientific American October 1988
Vif
 Vif = viral infectivity factor
 A basic ~23,000 kD phosphoprotein
 Required for efficient HIV-replication in primary T
cells
Differential Infection of Permissive and
Nonpermissive Cells by Vif HIV-1
2004;10:391
Expression of CEM15 in CEM-SS Cells
Selectively Inhibits HIV-1 vif Replication
From Sheehey et al.
Nature 2002; 418, 646 - 650
Vif Sequesters APOBEC3G Permitting
Production of Infectious HIV
Questions to Consider
 How does HIV-1 use the efficiency of the immune
system to efficiently infect and destroy the immune
system?
 What features of HIV-1 replication permit it to evade
the immune system as well as to become resistant
to antiretrovirals?
 How is HIV-1 replication regulated to synchronize
its replication to that of its host cell?
 What molecular mechanisms are used by HIV-1 to
evade innate anti-viral cellular responses?