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Structured Treatment Interruptions Workshop Summary

January 31, 2001

Progress in STI Research:
New Methods and Assays

Interlude Talks - III
Rodney Phillips, MDDS, FRCP, MD, MA
John Radcliffe University, Oxford, UK

Immunology from SSITT (Swiss/Spanish Study Intermittent Therapy Trial): "STI: Impact on HIV-1-specific cellular immunity: A preview of plans for immunology analysis of data from 120 patients in the SSIT study."

Antigen-specific T cells can be visually identified and counted with tetramers but this doesn't tell you what the T cells can do. In our analysis, we describe optimal CTL epitope peptides with known HLA restrictions, and then screen 10 to 30 peptides at each time point of analysis.

We've observed enhancements in some patients. One patient started with very little reactivity, but with viral recrudescence, there was some stimulation. When virus was re-suppressed, CD8+ cell counts went down. Other responses were not boosted. Using tetramers, we observed the expression of a specific CTL clone increase from 0.2% to 7% -- "nearly the highest I've ever seen in my work at Oxford. Whether it's doing any good is another question."

Another patient started with a very limited response to a number of peptides. Each STI resulted in boosted responses; by the end of the fourth interruption we saw many more responses with a very respectable ELISPOT result. We looked at tetramers to three epitopes in the same patient and observed respectable levels, indicating that the SSITT protocol is boosting the frequencies of CTLs that give only a modest ELISPOT functional response. We're seeing a discrepancy between boosted numbers versus boosted function.

In a third patient with 400 CD4+ cells and low viral load we saw no viral recrudescence and no CD8+ boosting. "Some times you see no benefit at all."

Certainly the results to date are far from definitive.

Julianna Lisziewicz, PhD
RIGHT Institute, Washington, D.C.

An experimental assay to quantify HIV-1 Virus-specific Immune Response (VIR) mimics viral rebound in vitro then measures IFN-gamma expression of CD4+ and CD8+ cells. VIR correlates well with treated, untreated and intermittently treated patients in cases when viral load and CD4+ count do not. In SIV251 infected macaques, VIR is absent when viremia is controlled by HAART and VIR is present when STI is performed.

The "Washington Patient" was treated then had five interruptions with an increasing duration off drug. VIR increased with each successive interruption from 2% to 5.7%. CD4+ and C8+ cell counts did not correlate with the interruptions. VIR detects functional (perforin producing) CD8+ cells and correlates with the duration of immune control.

Sebastian Bonhoeffer, PhD
Friedrich Miescher Institut, Basel, Switzerland

A population dynamics model of HIV replication kinetics suggests that STI can produce immune control without inducing drug resistance under certain conditions.

Prior to treatment with HAART, there is equilibrium between infected and susceptible CD4+ cell population counts. The ratio of CTL to infected CD4+ cells is also steady.

During treatment, this balance is shifted by an increase in virus-susceptible uninfected CD4+ cells and a dramatic decrease in the number of infected CD4+ cells. CTLs also decrease slightly and the ratio of CTL to infected CD4+ cells is shifted in favor of CTLs.

If, after interruption of treatment, HIV-1-specific effector cells outnumber infected cells, the model suggests that immune control of viral growth can be achieved. A negative viral growth rate results when the infected cells are removed by cell death or immune-mediated killing at a faster rate than they are produced.

Growth rate = infection - death - immune killing

For this to occur, the number of effectors must increase during treatment to a stable level higher than baseline at the start of treatment. At the time of TI the number of effector cells should more than outnumber new CD4+ target cells.

The model also addresses concerns about developing resistance during STI and concerns that viral reservoirs will be repopulated during viral rebound. A greater risk of resistance arises from drug-resistant mutants present in the viral population at the start of therapy than from newly generated mutants after rebound, as long as the viral load remains below baseline during STI. Similarly, refilling of latent reservoirs is unlikely if the rebound viral load during STI remains below the baseline pre-treatment level.

To evaluate clinical data from STI trials, it will be crucial to have accurate measurements of effector cell populations before, during and after therapy.

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