Viral tropisms • Cell tropism • Tissue tropism • Organ tropism • Species tropism
Impact of tropism 1. Transmission. 2. Replication. 3. Pathogenesis.
Tropism requirements • 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 • 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. • 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 immunoglobulin-like domains HIV envelope binds to a charged ridge on the outer domain
CCR5 and CXCR4 CXCR4
B HIV fusion and entry A 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 R5 Naïve T-cells High CXCR4+ CCR5- 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 R5 viruses are preferentially transmitted and predominate in immune tissue throughout disease non-mac-tropic mac-tropic
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? Immune tissue Non-macrophage-tropic
Selection pressures for non-mac-tropic R5 Envs • T-cell tropism? BUT mac-tropic R5 Envs mediate T-cell infection at least as well as non-mac-tropic Envs • Neutralizing antibodies? BUT R5 viruses in the acute phase are non-mac-tropic when there are no antibodies • 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 TAD Trimers are tightly closed in immune tissue V1 loop yellow V2 loop green V3 loop orange In brain, a trimer association domain epitope is often modified Helps expose the CD4 binding site and facilitate CD4 interactions
Summary • R5 viruses in immune tissue need high levels of CD4 for infection limiting their tropism to T-cells. • Enhanced binding to CD4 in brain tissue enables HIV-1 R5 viruses to infect macrophages which express low CD4. • Neutralizing antibodies force the HIV-1 Env into a tight trimer, limiting access to CD4 in immune tissue • Other unknown selective pressures may also be active in the periphery that are absent in brain tissue.