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Controversies in HIV Cure Research

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

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  1. Controversies in HIV Cure Research Mario Stevenson Ph.D University of Miami Miller School of Medicine. “There is ongoing replication under HAART”

  2. A spirited debate!

  3. 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.

  4. Viral surrogates in suppressive HAART? • Sequence evolution • Immune activation/inflammation • Latently infected cell frequency • Cell-associated viral RNA • Residual viremia • cDNA intermediates

  5. Cytoplasm ~10% Nucleus

  6. Cytoplasm   Raltegravir  Nucleus

  7. Episomes increase upon Raltegravir intensification. Buzon et al., Nature Med. 2010

  8. 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 

  9. 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.

  10. de novo infection: ongoing versus chronic infection.

  11. de novo infection: ongoing versus chronic infection.

  12. Let’s ponder the issues and hopefully, come up with a rational game plan.

  13. Intrinsic stability versus replenishment Time to eradication intrinsic stability Infectious virus replenishment 0 0 20 40 60 Years on completely suppressive HAART

  14. 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.

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