Structured Treatment Interruptions Workshop Summary

Progress in STI Research:
The Outlook for Immune Response

The State of the Hypotheses for STI

Primary Infection

Chronic Infection, Suppressed Virus

Chronic Infection, Unsuppressed Virus

Outstanding Immunology Issues

There is a crucial need to standardize:

• Immune-related HIV assays [HIV strains, viral peptides, VIR]
  

• Cell collection, storage and shipping protocols.

Correlate new assays with standard assays

• Correlate new immune markers (other than CD4+) with clinical endpoints and with virology endpoints.
  

• Fund immunology substudies of large clinical trials to standardize assays
  

• Correlate assay results with clinical events
  

• Correlate assay results in different populations
  

• Take advantage of the DAIDS repository and immunology QA funding.
  

• Use chip technology for multiple assay analysis.
  

• Collect samples and save cells.
  

• Obtain informed consent to save cells for future testing, including genetic analysis.

Expand the use of animal models

• To investigate the ideal duration of STI in primary infection.
  

• To correlate memory and naive cell numbers/ratios with disease progression or remission.
  

• Are enough animals available and accessible?

Investigate

• Host genomics
  

• Humoral immunity
  

• Cell collection, storage and shipping protocols.
  

• Investigate how memory/effector cell ratio influences the outcome of STI.
  

• Continue to look for ways to stimulate immune control during chronic infection.
  

• Continue to investigate cytokines and therapeutic vaccines.

Outstanding Virology Issues

What are the virologic determinants for HIV-1-specific immune stimulation?

• Amount (dose) of viral antigen

• Duration of exposure to antigen

• Viral genotypic and phenotypic variation during the interruption. What is the impact of viral evolution
  during STI?

• What are the best doses and durations for ´prime-boost' approaches? While there may be a lower and higher level of antigen necessary for these responses, they remain undefined. 50,000 should be enough in PHI (Altfeld), there is less data for CHI.

• Should durations be set by patient-oriented schedules, by fixed schedules or by fixed thresholds? Treat as viremia rises, allow VL to peak then go down, or treat when the CD4+ threshold is reached?

• Ongoing trials and animal models may help pinpoint these numbers.

• Could you predict the rebound magnitude based on pre-STI replication rates?

• Do immune-suppressive viral proteins that accompany the viral rebound affect immune response functions and complicate existing models?

Virus rebound -- Immunogenic stimulus

• What degree of viral control should be observed to accept the hypothesis that HIV-1-specific immunity can be stimulated? <50, <500, <5000 copies/mL? A relative drop? -1.0 log, -2.0 log? A lower setpoint than the pre-therapy setpoint? (Pre-therapy setpoints are difficult to determine.)

• In PHI there is no pretreatment setpoint to compare with.

• The risk thresholds for CD4+ or VL vary by opinions on "when to start" in CHI. How long does one wait to see VL rise then spontaneously fall? (Some suggest waiting 12 weeks off drug). Is there a viral threshold considered too risky to continue beyond? (Peak viremia is usually reached by week 7.)

• Why would one use an arbitrary viral load copy number as a trigger to restart treatment rather than CD4+ cell counts? It may depend on the governing hypothesis - or on what one's IRB will allow.

Virus rebound -- Antigenic stimulus

• What is the rebounding virus population?

• Does the cellular source of the rebound virus matter in terms of "immunogenicity" and/or "antigenicity"? There is usually more heterogeneity in the viral populations during CHI than in PHI. Reservoirs are critical for reseeding the rebound. (ADARC and NIAID are looking at this.)

• Is viral control on HAART associated with an SI-NSI switch? This could be measured.

• Do chemokine receptor expression, activation markers, cytokines, or antibodies affect or reflect response?

• Can there be an expansion of pre-existing drug-resistant minorities?

Drug exposed virus -- Drug pressure

• Viral evolution continues if drug pressure is maintained

• One benefit of STI is to stop the further accumulation of resistance mutations.

• It is possible to allow the outgrowth of WT virus. But who shifts from drug resistant to WT virus and what are the predictors of this switch?

• What is the impact on virus fitness, virulence, or pathogenicity? Are in vitro fitness or competitive outgrowth assays relevant?

• Do so-called compensatory mutations actually compensate?

• MDR HIV is highly impaired in replicative capacity but the virology is unclear. Should treatment be terminated? In which patients, for how long?

• Yet MDR HIV can be transmitted and replicate to a high level.

• What is the immunologic and clinical impact of a shift to WT as the dominant population?

• What are the costs of this switch in terms of CD4+ cell loss and clinical endpoints?

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