How does the HIV virus direct the host’s immunity against its own CD4 positive T cells ?
1. SPEAKER
ROHIT KUMAR
Ph.D 1st Year
Regn. No. 16-P-BT-02
Credit seminar
on
How does the HIV virus direct the host’s immunity
against its own CD4 positive T cells ?
2. INTRODUCTION
• HIV is a retrovirus with ssRNA.
• HIV infects cells that carry the CD4
antigen on their surface.
• Co-receptor CXCR4 and CCR5.
• T-tropic strains use the CXCR4 co-
receptor whereas M-tropic strains use
CCR5.
3. HIV-1 envelope glycoprotein (Env)
• The HIV-1 Env trimer is derived from proteolytic cleavage of gp160.
• It is composed of gp120 exterior and gp41 transmembrane subunits.
• Significant levels of soluble gp120 were found in blood and tissues of HIV
infected individuals.
• Binding of gp120 and CD4 exposes CD4i epitopes.
• CD4i epitopes are targeted by ADCC mediating Ab.
4. Virus directing host ADCC response towards
uninfected cells
ADCC mediating Ab
gp120
CD4
Lytic enzymes
CD4
downregulation
gp120
shedding
5. Nef & Vpu mediated downregulation of CD4
• Nef and Vpu are accessory viral
proteins.
• Nef enhances internalization of
surface CD4 and targets it for
lysosomal degradation.
• Vpu targets the newly synthesized
CD4 receptor for proteasomal
degradation.
Nef mediated downregulation of CD4 & MHC-I
6.
7.
8. gp120 shedding
• The gp120 exterior subunit is retained on the trimer via labile, non-covalent
interactions with the gp41 ectodomain.
• Spontaneous dissociation of gp120 from gp41, known as gp120 shedding.
• gp120 shed by infected cells binds to the CD4 receptor of uninfected cells.
• gp120–CD4 interaction results in exposure of CD4i epitopes.
• Host ADCC responses are directed toward uninfected cells.
9. A32 binds more efficiently to GFP- as
compared to GFP+ in case of WT infected T
cells.
ADCC-mediating Antibodies Recognize Uninfected T
Cells
A32 binding is significantly higher in GFP-
uninfected cells.
Richard et al., EBioMedicine, 2016
10. Serum binding in HIV+ & HIV-
Serum binding experiment: samples from 10 HIV+ and 5 HIV- individuals.
Richard et al., EBioMedicine, 2016
11. Shed gp120 are the major source of Env on
uninfected cell
Richard et al., EBioMedicine, 2016
12. Cell-cell contact is not required for the presence of
gp120 on the surface of uninfected cells
Richard et al., EBioMedicine, 2016
13. HIV infected CD4+ T cells
eFlour 450 stained uninfected
CD4+ T cells
Cell-cell contact is not required for presence of
gp120 on the surface of uninfected cells
Transwell®
14. ADCC mediated killing of uninfected CD4+ T cell is higher
as compared to infected one
Richard et al., EBioMedicine, 2016
15. CONCLUSION
• CD4 downregulation in infected cells and binding of gp120 shed by
infected cells results in killing of uninfected CD4+ T cells.
• Vpu & Nef are responsible for CD4 downregulation.
• CD4-gp120 binding on the surface of uninfected cells is recognized by
ADCC mediating Ab.
Future propects:
• Development of CD4 mimicking compounds which can bind to gp120.
16. BIBLIOGRAPHY
• Maxime Veillette, Mathieu Coutu, Jonathan Richard, Laurie-Anne
Batraville, Olina Dagher, Nicole Bernard, Cécile Tremblay, Daniel E.
Kaufmann, Michel Roger and Andrés Finzia. The HIV-1 gp120 CD4-Bound
Conformation Is Preferentially Targeted by Antibody-Dependent Cellular
Cytotoxicity-Mediating Antibodies in Sera from HIV-1-Infected Individuals.
Journal of Virology, 2014.
• Nicolas Roy, GrégoryPacini , ClarisseBerlioz-Torrent and KatyJanvier.
Mechanisms underlying HIV-1 Vpu-mediated viral egress. Frontiers in
Microbiology, 2014.
• Jonathan Richard, Maxime Veillette, Shilei Ding Daria Zoubchenok Nirmin
Alsahafi, Mathieu Coutu, Nathalie Brassard , Jongwoo Park , Joel R. Courter,
Bruno Melillo, Amos B. Smith, George M. Shaw d, Beatrice H. Hahnd,
Joseph Sodroski , Daniel E. Kaufmanna and Andrés Finzi. Small CD4
Mimetics Prevent HIV-1 Uninfected Bystander CD4+ T Cell Killing Mediated
by Antibody-dependent Cell-mediated Cytotoxicity, EBioMedicine, 2016.
