from Jules Levin

At yesterday’s immune reconstitution session research additional and confirmatory of reported data at Chicago Retrovirus Conference said the immune system can be reconstituted although it’s variable between individuals. Researchers reported observing HIV specific CD4 responses from treating with HAART during acute infection. They reported increased responses to recall antigens from HAART treatment during chronic infection. Clearly, the immune system is capable of immune reconstitution. However, if a low CD4 (<100) is increased to say for example 300 due to HAART, OI prophylaxis should probably be continued. Although there is some data that this increased CD4 will protect from some Ois, data from ongoing studies may be required to make sound medical decisions abut discontinuing therapy.

At this morning’s just completed Plenary session on Pathogenesis and Reservoirs, Anthony Fauci said curing a retrovirus is a remarkable concept because the virus integrates itself into the host cell reproduction process. But, HIV may be containable by regulation of cytokines with HAART. As you may know Siliciano and others have reported a virus reservoir of latent replication competent HIV in resting memory CD4 cells that so far seems to persist. Ho says he observes decay but Silician says he doesn’t. Fauci said he doubts we could eliminate this reservoir but we may not have to. He thinks purging this reservoir may be possible and that would diminish the pool size although not eliminating it. He said HAART plus cytokine therapy may accomplish this. His in vitro experiments show a lessening of the size of this pool when combining HAART with cytokine therapy. However, to test hypothesis individuals would have to stop therapy at some point. David Ho and others are exploring the possibility of emptying this reservoir with cytokine therapy.

Robert Siliciano first reported this reservoir and spoke this mornig about it. The reservoir is very small: <.01% of resting CD4; about 1 per million cells. But, represents a pool of virus that he so far has not yet seen decay. He and Fauci said that this reservoir appears to be established early after infection and treatment during acute infection would not prevent its establishment.

Siliciano went on to give reasons for hope about this reservoir and treatment:

• the size of the pool may be reduced and I think he said the decay accelerated (I will check notes on this) if treatment is started early. He saw a smaller reservoir when individuals were treated during acute infection with hydroxyurea (HU) regimen. He is not sure if its due to HU or early treatment or both.
• this reservoir could decay with additional ime. We’ve only been following it for a few years
• the pool may be getting replenishment from low level viral replication, which could mean decay is occurring
• there is no evidence of drug resistant mutations in reservoir
• it is not yet clear if virus in reservoir would rekindle replication if treatment is stopped
• 1 patient who received HU regimen remains without detectable plasma virus despite stopping therapy. Latent virus was detectable in this person but at a low level.
• the reservoir is hard to detect in some patients treated with HAART in late stage disease
• strategies mentioned above to activate and deplete reservoir are being explored
• "eradication is not a myth". It may be possible although there may be additional reservoir we have not yet identified. See NATAP Repots May ‘98 edition for full discussion of viral reservoirs, immune reconstituion and HIV specific CD4 responses.

David Ho spoke next in the Viral and Cellular Dynamics Section. As I reported in NATAP Reports, Ho said at Retrovirus Conference that he observed decay in latent pool described above. He said here in Geneva he observed decay of this pool in 8 individuals treated during acute infection. Siliciano’s group were treated during chronic infection. He computes a halflife decay rate of 5-6 months which is in line with the decay rate of memory cells in general. But, he also observed a variable decay rate and in two individuals saw no decay.

At months 16 and 20 he observes viral evolution but no drug resistance suggesting to him that there is ongoing viral replication despite apparent undetectable viral load in plasma. The good news is that this suggests the challenge of eradication may not be one of latency but could be one of additional potency required of the drug therapy ("HAART may not be hard enough") or possibly immune based therapy plus HAART could increase HIV specific immunity to control HIV. Intensification of HAART may be required to increase potency of treatment to stop this ongoing replication.