Controversies in HIV Cure Research

Mario Stevenson Ph.DUniversity 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

Nucleus~10%

Cytoplasm

Nucleus

Raltegravir

Episomes increase upon Raltegravir intensification.

Buzon et al., Nature Med. 2010

Raltegravir

Therefore, an increase in episomes following Raltegravir intensification can only be explained by de novo infection.

An increase in episomes requires:

- infectious virions.- de novo viral synthesis of viral cDNA

• The low level of replication may be insufficient for resistance development.

• A chronic virus source drives limited rounds of infection.

If there is continued infection under HAART, why don’t we see development

of resistance?

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.

Years on completely suppressive HAART

Infe

ctio

us v

irus

Intrinsic stability versus replenishment

Time to eradication

6040200

intrinsic stability

replenishment

0

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.