Progress in STI Research:
The Outlook for Immune Response
The State of the Hypotheses for STI
|Treat briefly to lower the viral setpoint
and allow people to live longer with less drug exposure.
||We have anecdotal evidence that this is possible.
||Determine long-term benefit and safety.
Chronic Infection, Suppressed Virus
|Attain remission through HIV-1-specific immune control.
||There is evidence that this occurs in some patients.
||Identify responders and increase the proportion that responds.
|Get acceptable clinical
results with less drug exposure and prevent death and disease.
||There is evidence that abnormal lab values
can recover during interruption; there is little evidence that drug-related
symptoms recover, at least during the short interruption periods studied
||Identify patients for whom this is safe.
Chronic Infection, Unsuppressed Virus
|Reduce toxicity by periodically
stopping drug treatments.
||There is evidence that abnormal
lab values can recover during interruption; there is evidence that
fat redistribution does not improve.
||Practice careful medical
management to minimize the risk of clinical events in patients with
low and declining CD4+ cell counts.
|Re-sensitize the virus to
antiretroviral drugs so patients can avoid death and disease by returning
to therapy and suppressing virus. The goal should be to maintain CD4+
cell counts and preserve immune repertoire.
||There is evidence that shift to WT virus
can occur -- but drug susceptibility is eventually lost when therapy
is reintroduced. Time required for shift to WT usually results in
significant CD4+ cell count declines. These declines are greatest
in those with higher CD4+ counts.
Identify patients for whom this is safe.
Identify patients for whom this can be predicted.
Outstanding Immunology Issues
There is a crucial need to standardize:
- Immune-related HIV assays [HIV strains,
viral peptides, VIR]
- Cell collection, storage and shipping
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
- 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?
- 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
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
- 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
- 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
- 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
- One benefit of STI is to stop the further accumulation of resistance
- 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
- 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
- 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
- What are the costs of this switch in terms of CD4+ cell loss and clinical
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