1. HIV Cure: Current Status and Future Perspectives
Giuseppe Pantaleo, M.D. Professor of Medicine Head, Division of Immunology and Allergy Executive Director, Swiss Vaccine Research Institute Lausanne University Hospital, Lausanne, Switzerland

2. HIV Cure: Definition and Potential Outcomes
Eradication
Functional cure
Elimination of all HIV infected cells containing HIV Integrated DNA
Elimination or control of cells containing replication competent virus
Berlin Patient
Elite controllers, Post cART controllers

3. Why Hiv persists? Three Main Mechanisms Virologic Immunologic
Therapeutic

4. Two Main Hypotheses Not Mutually Exclusive Residual HIV replication
Virologic Mechanisms
Two Main Hypotheses Not Mutually Exclusive
Latent HIV reservoir
Residual HIV replication
CD4 T cells?
Macrophages?
DCs?
TCM/TTM
CD4 T cells
Size: estimated 106 cells
Half life of memory CD4 T cells: 44 months
Estimated time for eradication: ~70 years under full virus suppression by ART
Not susceptible to ART
Not susceptible to the immune system
Privileged anatomical compartment
Resistant to HIV cytopathic effect
Poorly accessible to cytotoxic CD8 T cells
Minimal virus spreading
Replenishment of the latent cellular reservoir
Wong et al., Science 1997; Finzi et al., Science 1997
Chun et al., Nature 1997; Siliciano et al., Nature Med 2003
Lorenzo et al., Nature 2016
Yukl et al., AIDS 2010

5. Immunologic Mechanisms Privileged Anatomic Compartments/
Main Hypotheses
Privileged Anatomic Compartments/
T-cell Activation
Limited localization
of HIV-specific
CD8 T-cells

6. Productive SIV Infection in Tfh Cells within Germinal Centers of Elite Controller Macaques
Chronic Progressor
SIV RNA+ cells within B cell follicles 6
Fukazawa et al., Nature Med 2014

7. Immunologic Mechanisms Privileged Anatomic Compartments/
Main Hypotheses
Privileged Anatomic Compartments/
T-cell Activation
Limited localization
of HIV-specific
CD8 T-cells

8. Limited Localization of HIV-Specific CD8 T Cells within Germinal Centers
PT# 1
Pt# 2
Pt# 3
Connick et al., J immunol 2007

9. Therapeutic mechanism: Long-Term cART Fails To Eradicate HIV Infection
Initiation of ART
HIV viremia
Limit of detection
Cessation of therapy
Time

10. What Is the Target?

11. HIV Functional Cure: Targeting of Cells Containing Replication Competent Virus
Ho et al., Cell 2013
Bruner et al., Nature Med 2016
Hosmane et al., JEM., 2017
Total DNA
Intact
QVOA
Total frequency of HIV infected cells containing HIV DNA
Integrated
DNA
Total frequency of HIV infected cells measured by Alu PCR assessing Integrated HIV DNA
Total frequency of HIV infected cells containing full intact HIV provirus
Total frequency of HIV infected cells containing inducible replication competent virus as assessed by quantitative viral outgrowth assay
INT DNA
PCR-based
Defective
Sequencing
Intact,
non-induced
Culture-based

12. Lymph node PD-1+/Tfh Cells Are the Primary Cell Reservoir for Replication Competent and Infectious HIV-1
120
150
100
96% 80
100
Contribution of each population to
the total pool of cells containing
replication competent virus (%)
46%
Contribution of each population to
the total pool of cells contnining
infectious virus (%) 60 40 50 20
CXCR5
PD-1 – + – +
CXCR5
PD-1 – + – +

13. WhERE To Target?

14. Unit of HIV Production and Persistence in ART Treated Patients
Germinal Centers Are the Primary Site for Production and Persistence of HIV
HIV Production Unit
in Viremic Patients
Major Source of
Plasma Viremia
Germinal Center
FDC
HIV
B cell
Light zone
Reactivation of
latently infected
TFH cells
Activation
TFH
HIV Particle
Pre-GC
TFH cell
Dark
zone
Centroblasts
proliferation
Unit of HIV Production and
Persistence in ART Treated Patients
Source of
Virus Blips
B cell
Reactivation of
latently infected
TFH cells
Activation
TFH
Pre-GC
TFH cell
Centroblasts
proliferation

15. Solutions

16. Combined Biologic Interventions
PD-1
HDACi
CD4
Nef
Activation of HIV Replication
Nef
Nef
Potentiation
Potentiation
HIV
Nef
Nef
ADC: PD-1 or HIV env
Or bNabs
Therapeutic Vaccine
i.m.
Nef
Reactivation/Boosting
HIV Replication
i.v.
Generation / Boosting of
HIV-specific
CD8 T-cells
Killing of HIV infected
CD4 T-cells

17. RNA change (log10 copies/μL)
cART Paradigm for Combined Biologic Interventions (cBI) To Achieve ‘HIV Functional Cure’
Single BI
Dual cBI
Triple cBI
RNA change (log10 copies/μL)
Therapeutic vaccine +
bNabs +
other Abs (Reservoir
Depletion?) or
immune stimulators or
HDACis
Therapeutic
vaccine or
single bNab
Therapeutic
vaccine +
bNabs
24 weeks

18. Acknowledgements
This project has received funding from the European Union’s horizon research and innovation programme under grant agreement No
This project has received funding from the Swiss government (through the State Secretariat for Education, Research and Innovation, SERI) under grant agreement No The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government.