"towards a cure”: hiv reservoirs and strategies to control them
TRANSCRIPT
"Towards a Cure”:
HIV Reservoirs and Strategies to Control Them
IAS WORKSHOP, 16 & 17 JULY 2010
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
HIV-1 Reservoirs and Sanctuary Sites
Satya Dandekar
University of California , Davis
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA HAART: Success in HIV Research
•Suppression of viral loads and enhanced immune functions
•Increased life span and clinical benefits
•Prevention of mother-to-child viral transmission
HAART: Challenges
•Viral suppression but not eradication
•Persistence of the viral reservoirs that are latent but have
replication-competent HIV genomes, molecular mechanisms
in operation to suppress viral replication,
•Low level viral replication at tissue anatomic sites despite
HAART
•Incomplete immune recovery
•Incomplete resolution of immune activation
•Reactivation following therapy interruption
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA HIV Biology and Early Host-Viral interactions
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
Ac u te H I Vr e v is i te d: n e w o p p or t u n i t i e s f ortr e a tm e n t a n d pr e ve n t i o n, P i lc he r e ta lJ. C l in . I n v e s t. 1 1 3: 7 do i: 1 0. 1 1 7 2 /J C I 2 1 5 4 0
ENTRY
SEEDING
DISSEMINATION
HIV-1 Mucosal Transmission and Systemic Dissemination
Primary HIV infection: active viral replication, robust immune
response, cell killing, tissue damage
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
Ac u te H I Vr e v is i te d: n e w o p p or t u n i t i e s f ortr e a tm e n t a n d pr e ve n t i o n, P i lc he r e ta lJ. C l in . I n v e s t. 1 1 3: 7 do i: 1 0. 1 1 7 2 /J C I 2 1 5 4 0
ENTRY
few HIV-1 variants transmitted
SEEDING
viral amplification
DISSEMINATION
similar viral population in early infection
viral divergence and compartmentalization in
advanced/chronic HIV infection
HIV-1 Mucosal Transmission and Systemic Dissemination
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IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
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IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA HIV-1 Infection of macrophages and microglia in
Brain
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Gonzalez-Scarano et al 2005 Nature Rev Immunol 5:69
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
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IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
Questions about HIV reservoirs
1. Is there ongoing residual viral replication in tissue compartments during
HAART? What is the size of latent viral reservoir during HAART? How
does it differ among different tissue compartments?
Despite long term HAART, viral RNA can be detected in gut biopsies
and plasma samples.
2. Will homeostatic proliferation of latently infected cells lead to the
maintenance/expansion of this pool?
During long-term HAART, patients with >60% gut mucosal CD4+ T cell
restoration had suppressed HIV RNA loads but maintained HIV DNA
load.
3. Can the residual viral replication be completely suppressed by HAART
intensification? Is there demonstrable benefit beyond certain thresh-
hold of viral suppression?
4. Better phenotypic characterization of the cells that are latently HIV
infected?
CD16+ monocytes with proinflammatory nature are infected with HIV.
Cell surface markers can be better defined.
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA
Homing from periphery
Treg cell
MUCOSA
Th17 cell
IL-10
IL-12
IL-4
Th1 cell
Antigen
loaded DC
Enteric
pathogens
SIV
Luminal
Bacteria
Questions about tissue microenvironment
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA Questions about tissue microenvironment
1. Will initiation of HAART early in infection restore CD4+ T cells and anti-
viral functions at the mucosal sites? Will this provide better control of the
immune activation? Will it reduce the burden of latent viral reservoir?
•Initiation of therapy during primary SIV infection led to effective restoration
of gut mucosal CD4+ T cells and anti-viral mucosal T cell responses.
2. Can efforts to accelerate gut mucosal epithelium recovery be beneficial
for mucosal immune response to HIV and other pathogens?
•HIV induced gut mucosal damage may slow epithelium repair and
regeneration.
3. What is the role of gut mucosal innate responses in aiding HIV
suppression?
•Expression of anti-microbial and anti-viral molecules are critical in mucosal
protection. Innate responses are important components of mucosal
immune response.
IAS HIV RESERVOIRS W
ORKSHOP, 16 & 17 JULY 2010, VIENNA Utility of the Simian immunodeficiency virus model
Availability of combination therapy for the analysis of viral reservoirs, their
size and locations.
Suitable for evaluating effects of early HAART initiation on viral reservoirs
and anti-viral immune responses in tissue compartments
Valuable for using novel approaches to repair the gut epithelial damage and
evaluate any benefit in preventing microbial translocation and leakage of
microbial products
Appropriate for evaluating early initiation of therapy with therapeutic
vaccines.