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Structured Treatment Interruptions Workshop Summary

January 31, 2001

Interlude Talks - I
Genoveffa Franchini, MD
National Cancer Institute, NIH, Bethesda, Maryland

Twenty-four macaques were infected with SIV251 then divided into 3 groups of 8 animals each. Groups A and B received HAART; Group C received no antiretroviral therapy. Groups B and C received vaccinations with NYVAC–SIV-gpe; Group A received a mock vaccine.

A vaccinated macaque infected with SIV251 can continuously suppress viral replication. However, even slow progressors will still develop disease.

  • Can HAART reconstitute an immune response to SIV?
  • Can vaccination enhance the immune response?
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  • Can vaccination contribute to viral containment after HAART?

If treated during primary infection:

HAART alone (Group A) Poor suppression off drug
HAART plus vaccination (Group B) Better suppression off drug
Vaccination alone (Group C) OK suppression off drug [better than HAART alone, worse than HAART+vaccine]

By a tetramer staining assay, 5.7% of CD8+ T-cells responded to gag epitopes. Vaccination expanded gag-specific responses even when virus was suppressed. The results were inversely correlated with viremia: Better vaccine response was associated with better viral suppression. After interruption, better control of viremia was associated with better suppression while on HAART.

If treated during chronic infection:

  • Only animals with >1000 CD4 cell counts responded, suggesting that IL-2 may be needed to enhance immunogenicity.
  • IL-2 increased the number of CD8+ effector cells producing IFN-gamma when stimulated by vaccination (NYVAC).
  • IL-2 increased the number of functional virus-specific CD8+ cells. Low dose IL-2 contributed to suppression of viremia.
  • Vaccines may be more effective than endogenous vaccination if replication in the gut is enhancing the response.

Franco Lori, MD
RIGHT Institute, Washington, D.C.

A comparison of three treatment strategies for SIV infection in macaques makes clear the advantages of animal models for demonstrating concepts.

In primary SIV infection but not chronic infection, STI resulted in durable viral control after treatment discontinuation.

Within six weeks of infection, animals were treated with either continuous HAART, HAART on a 3 weeks on/3 weeks off schedule, or left untreated.

Continuous HAART-treated and intermittent HAART-treated monkeys had equivalent viral load and CD4+ percentages after several cycles of STI.

During the first interruption, all of the HAART/STI monkeys had viral rebound; by the fourth interruption, no monkeys rebounded. After permanent discontinuation of HAART, continuously treated animals had immediate rebound while HAART/STI animals remained suppressed at 41 days. Continuous HAART animals experienced insulin resistance and pancreatitis; HAART/STI animals had no serious toxicity.

A similar study in chronically infected macaques was less encouraging. Continuously treated animals remained suppressed while on HAART but animals treated with a HAART/STI schedule experienced rebound after each interruption.

Deborah Persaud, MD
Johns Hopkins University, Baltimore, Maryland

Reservoirs of HIV-1 exist despite effective suppression on HAART. Resting CD4+ cells hold an archive of viral mutations. Those on sub-optimal therapy probably have some resistant virus archived. Resting CD4+ cells can divide and release archived virus to the plasma even without antigenic stimulation. This explains the persistence of founder viral strains and also explains observations that each viral bloom can be genomically different.

One clinical implication of the persistence of viral mutants is that recycling drugs to treat a rebounding wild type virus after interruption will probably fail in most cases.

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