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Controversies in HIV Cure Research
Mario Stevenson Ph.D
University of Miami Miller School of
Medicine.
“There is ongoing replication under HAART”
A spirited debate!
What accounts for the extreme
persistence of the viral reservoir?
• HAART stops all viral replication. Reservoir
persistence is due to the intrinsic stability of the
latently infected, resting CD4 T-cell.
• Residual replication continues due to
incompletely suppressive HAART. Reservoirs
are maintained by replenishment.
Viral surrogates in suppressive
HAART?
•
•
•
•
•
•
Sequence evolution
Immune activation/inflammation
Latently infected cell frequency
Cell-associated viral RNA
Residual viremia
cDNA intermediates
Cytoplasm
~10%
Nucleus
Cytoplasm

Raltegravir 
Nucleus

Episomes increase upon Raltegravir
intensification.
Buzon et al., Nature Med. 2010
An increase in episomes requires:
-

Raltegravir 
infectious virions.
de novo viral synthesis of viral cDNA
Therefore, an increase in episomes
following Raltegravir intensification can
only be explained by de novo infection.

If there is continued infection under
HAART, why don’t we see development
of resistance?
• The low level of replication may be
insufficient for resistance development.
• A chronic virus source drives limited
rounds of infection.
de novo infection: ongoing versus chronic infection.
de novo infection: ongoing versus chronic infection.
Let’s ponder the issues and hopefully, come up
with a rational game plan.
Infectious virus
Intrinsic stability versus replenishment
Time to eradication
intrinsic stability
replenishment
0
0
20
40
60
Years on completely suppressive HAART
Monitoring the impact of treatment
intensification:
• INTegRAL study by J. Picado, B. Clotet et al:
impact of Raltegravir intensification.
• 69 patients on suppressive 3 drug HAART
regimen randomized to intensify with Raltegravir
(n=44) or to continue HAART (n=24).
• Episomal cDNA and immune activation
parameters were monitored.