Viral tropisms
1.
2.
3.
4.
Cell tropism
Tissue tropism
Organ tropism
Species tropism
Impact of tropism
1. Transmission.
2. Replication.
3. Pathogenesis.
Tropism requirements
1.
2.
3.
4.
Appropriate receptors on cells for attachment and entry.
Cells must be permissive for all steps in replication.
Access to tissue, organ.
The virus may need to evade host innate and adaptive
immunity.
Determinants of Retroviral Tropism
1. Any stage of the replication cycle that requires host
proteins.
---envelope/ receptor interactions.
---promoter sequences adapt for optimal transcription.
2. Whether a host cell event is required.
---many retroviruses require cell division.
3. Host immunity
---host antibodies may select for variants that are
neutralization resistant. Immunoprivileged sites may
select for other variants.
---intrinsic restriction factors; HG
HIV receptors and tropism
---All HIV strains bind CD4.
---a second receptor or coreceptor is needed to
confer infection.
---Coreceptors are members of the chemokine
receptor family.
CD4
Four immunoglobulinlike domains
HIV envelope binds to
a charged ridge on the
outer domain
CCR5 and CXCR4
CXCR4
HIV fusion and entry
A
B
VIRUS PARTICLE
gp41 TM
gp120 SU
CD4
CORECEPTOR
CELL SURFACE
C
D
6-helix bundle
HIV-1 phenotypes and disease
Acute
AIDS
Asymptomatic
R5 virus
R5X4, X4
50% of AIDS patients
CXCR4-using variants detected in up to 50% of AIDS patients
---driven by mutations in Env e.g. in the V3 loop
---lower frequency in clade C (≈5%)
HIV tropism
HIV infects CD4+ cells.
These include:
T-cells
macrophages
dendritic cells
HIV-1 R5 and X4 viruses target different cell
populations
R5 viruses infect T-cells and macrophages
X4 viruses infect T-cells
R5X4 are dual tropic, mainly T-cells
Coreceptor expression directs
differential HIV-1 tropism among CD4+
T-cells
Central memory T-cells
Low CXCR4+
Low CCR5+
CXCR4
-using
Naïve T-cells
High CXCR4+
CCR5-
R5
Effector memory T-cells
Low CXCR4+
High CCR5+
R5 virus tropism for macrophages
R5 viruses highly variable in capacity to infect
macrophages.
non-mac-tropic
mac-tropic
non-mac-tropic R5 viruses are preferentially
transmitted and predominate in immune
tissue throughout disease
CD4+ T-cells express much higher levels of CD4
compared to macrophages
Non-mac-tropic envs require high levels of CD4 for infection
Mac-tropic R5 envelopes have adapted to exploit low CD4
levels on macrophages
HIV-1 R5 viruses with different tropisms target
different tissues
---Non-mac-tropic R5 predominate in immune tissue and
periphery
---Mac-tropic R5 predominate in the brain
HIV in the brain
About 30% AIDS patients suffer severe neurological disorders
known as HIV-associated dementia (HAD).
Infected infants develop HAD earlier and more frequently.
HIV in the brain
---HIV enters the brain early after infection.
---Difficult to detect during the asymptomatic phase.
---Extensive replication usually observed late on in
HAD subjects.
---macrophages, microglia are the main cells targeted.
---mac-tropic R5 viruses predominate in the brain.
The brain is protected by the blood brain
barrier which usually excludes immunoglobulin
---very different environment compared to immune
tissue where HIV targets mainly T-cells and is
bombarded by neutralizing antibodies
R5 envelope variation
Macrophage-tropic
brain
Adaptation to T-cells or macrophages?
Neutralizing antibodies?
Other factors?
Non-macrophage-tropic
Immune tissue
Selection pressures for non-mac-tropic R5 Envs
1. T-cell tropism? BUT mac-tropic R5 Envs mediate
T-cell infection at least as well as non-mac-tropic
Envs
2. Neutralizing antibodies? BUT R5 viruses in the
acute phase are non-mac-tropic when there are
no antibodies
3. Other mechanisms? Non-mac-tropic R5 Envs
need high CD4.
---precludes infection of dendritic cells
Env trimer structure is different in brain tissue
Trimer association
domain
Trimers are tightly closed
in immune tissue
In brain, a trimer association
domain epitope is often modified
Helps expose the CD4 binding site
and facilitate CD4 interactions
TAD
V1 loop yellow
V2 loop green
V3 loop orange
Summary
1. R5 viruses in immune tissue need high levels of CD4 for
infection limiting their tropism to T-cells.
2. Enhanced binding to CD4 in brain tissue enables HIV-1
R5 viruses to infect macrophages which express low
CD4.
3. Neutralizing antibodies force the HIV-1 Env into a tight
trimer, limiting access to CD4 in immune tissue
4. Other unknown selective pressures may also be active
in the periphery that are absent in brain tissue.