Transcript From Rome to Addis - Basic Science

HIV Science Update from Rome
to Addis : Basic Science
Coumba Toure Kane
Dakar University Senegal
Introduction
• Basic science research valuable scientific
information
• Questions still remain about:
– the molecular interactions involved in the
regulation of HIV expression and replication in
human immune cells,
– why the host immune response is not fully effective
in controlling the infection, and
– how reservoirs of infection persist in the body
despite highly active antiretroviral treatment
(HAART)
Key Outcomes
• Prevention
• Mechanisms of disease progression
• Immune Activation /inflammation and HIV
disease
• Antiviral immunity and transmission
• HIV coinfection
• Drug developpmement and resistance
• Joint –Bridging sessions
• Reservoirs /strategies to eliminate reservoirs
Prevention
New prevention strategies
In the era of PrEP and treatment as prevention, do we
still need vaccine?
Vaccine:
• Given once
• Durable protection
• Cost-effectiveness
Prevention : Vaccine Research
• The changing face of HIV vaccine research
• some promising scientific developments
–high diversity of HIV envelope and the
importance of glycans, which mask HIV
envelope and creates an even more moving
and evasive target
–Development of resurfaced stabilized cores
that can be used as probes for Human
neutralizing antibodies and templates for
immunogens.
–VRC01 that not only neutralizes 90% of
natural circulating viruses but also confers
sterile protection against mucosal challenge
in non-Human primates.
Prevention : Vaccine Research
• The changing face of HIV vaccine research
• News from Bangkok Emerge Molecular Clues to
Explain First Successful HIV Vaccine Experiments:
Results of HIV vaccine ALVAC and AIDSVAX
Immune responses of patients could point way
forward for future vaccines.
Prevention:Time to consider a combination
approach to biomedical interventions
• Mucosal exposure in the context of PrEP influence immune
response (animal models)
• VAXPrEP could deliver better protection by providing protection
during immunization period, reducing infectious challenge, and
increasing eclipse phase providing an extended opportunity for
adaptive immunity to respond.
• Vaccine candidates can be co-formulated with
microbicides
– Gp120 stable within genital gels
– mucosal vaccination boost localized immunity
Mechanisms of disease progression
•Naïve T cell recruitment is not the major source of CD4+ memory T cell
production after infection; CD4+ memory T cells are intrinsically capable of
self-renewal
•Intestinal microbioma as driver of inflammation?
•Greater representation of proinflammatory/inflammation-thriving
class-level bacteria.
•Tryptophan catabolism as correlate of HIV disease progression and
mortality?
Lower pretreatment tryptophan predict slower CD4+ recovery after 12
months therapy; lower pretreatment/month 6 tryptophan predict death,
also adjusting for self-reported dietary protein intake
Immune activation/inflammation and HIV disease
The facts:
Immune activation predicts disease progression and response to
HAART;
Immune activation persists on virologically-suppressive HAART;
Immune activation/inflammation on HAART associates to noninfectious complications
The questions:
o What drives immune activation on HAART?
o How can we target immune activation as an anti-HIV therapy?
Immune activation/inflammation and HIV disease
How do we move forward?
Models of protection
Why do elite controllers have high T-cell activation but low HIV RNA?
Non-pathogenicity of SIV-1 for African monkeys (get infected, present
viremia, present immune activation only during acute infection0
Viral determinants of AIDS pathogenesi
Interventional trials
“Interventional Trials targeting key pathways of “activation” can
concurrently test hypotheses of pathogenesis and also explore
promising treatment strategies for persons at risk for morbidity”
(PANEL CONSENSUS)
Approaches to block inflammation/immune activation
Antiviral immunity and transmission
Antiviral immunity
Human stem cell-based gene therapy to engineer
HIV- specific T-cell immunity can elicit functional
anti-viral CTL in vivo
- Transmission
Non-human primate model of penile transmission (RMSIVMAC251): SIV can be transmitted by penile SIV
exposure but is ~50% less efficient than vaginal
challenge
HIV co-infections: the axis of the evil
•GBV-C /HIV
–GBV-C infection reduces B/NK activation and monocyte CCR5
surface expression
•HIV/ Toxoplasma gondii–Destruction of nervous cells is potentiated in the simultaneous
presence of gp41 and Toxoplasma gondii-
•HIV/Malaria
–Placenta malaria associated with increased risk of MTCT of HIV1 (aOR = 6.5; 1.4-30.9), especially among primigravidae (aOR =
12.0; 1.0-150; p< 0.05)
Drug development and Resistance
Tenofovir gel
1% Tenofovir gel (CAPRSA 004), has a direct antiherpetic activity:
(i) it inhibits HSV-1 and HSV-2;
(ii) reduces HSV-1 and HSV-2 replication at different sites;
Topical drug administration appears to be a key
requirement to enable this dual prophylactic effect of
tenofovir -
Joint Sessions (Track A and B)
–TB paradox
– Basic Sciences  Clinical
– investigating the signaling pathways involved
in unmasking TB pathogenesis. CREB pathway(s)
• Increased expression of cytokines and acute-phase
reactants regulated by the cAMP/CREB pathway
supporting the role for an activation of the CREB
pathway(s) in the pathogenesis of IRIS.
– new strategies to treat TB and MDR-TB in resource
limited settings and the importance of IRIS in the
approach to HIV ART and treating TB coinfection.
Bridging Sessions
• Drug resistance
– Basic Sciences  Operational Research
• Correlation : Emergence DR and Increased Risk of Mortality
• Clinical relevance of DR in both develpped and developping
countries Improvment of ART regimens to Prevent DR in
PMTCT
• Need of Population based surveillance of HIV DR  prevent
the Emergence of Resistance itself
• Need to setup patient’s adherence to treatment and setup
operationnal research to identify best clinical practise.
Reservoirs and strategies to eliminate
Reservoirs
•CCR6: marker for memory T-cells imprinted
with a transcriptional program favorable to HIV
replication
•Lymph nodes reservoirs and
alteration/dysregulation
•TH22 cells: gut HIV reservoir and immune
activation on HAART
Cure and eradication research
• comprehensive overview
– HAART cannot eradicate HIV infection and people on
HAART show significant higher prevalence of
morbidities, which may be linked with residual HIV
replication and immune activation.
– The reasons for finding a cure are multiple.
• Elite controllers and CCR5delta32/delta32 stem
cells transplantation  2 examples of respectively
• -non sterilising (functional) and sterilising cure.
Cure and eradication research
• comprehensive overview
– Latency, persistent infection and sanctuaries are
the causes of persistent HIV RNA production in
patients.
– Concerning the roadmap to a cure,
• intensification, therapeutic vaccination,
• elimination of latency infected cells and
• gene therapies are considered as possible strategies.
Implications for Africa
• interactions between the virus and the host immune
system, and implications in terms of AIDS therapy and
Prevention  Favourable Research environment ++++
– Prevention
• Commitment to a Highly active HIV prevention that can be
achieved by combination of behavioral changes, ART, social
justice and human rights, and Biomedical strategies
• More studies are needed +++ deliver of innovation
– Therapy
• Optimal management
• More studies +++ (from basic to operational Research)
• Assessment strategies and interventions
Conclusions
• ”Now let Science inform Policy”,
– referring in particular to HPTN 052 (96% reduction of HIV-infections in heterosexual
serodiscordant couples).
– The new scientific targets outlined are a
preventative vaccine (trying to solve the
dilemma: "Will a neutralizing epitotope also
be an immunogen?”) and a cure (sterilizing or
functional, that means no eradication but full
control without drugs).
Conclusions
• ”Now let Science inform Policy”,
– Basic scientific information is critical to
feeding the pipeline that generates new
targets against which therapeutic
interventions and vaccines can be directed.
Thank you for your attention