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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? .
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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”
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: • 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. Raltegravir
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.
Let’s ponder the issues and hopefully, come up with a rational game plan.
Intrinsic stability versus replenishment Time to eradication intrinsic stability Infectious virus 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.