therapeutic agent will invariably lead to complex and difficult-to-predict counterregulatory
responses, it is difficult to predict how such interventions will affect the viral reservoir. The complexity of attempting to use an activating agent
to reverse latency is illustrated by recent studies
with IL-7. Preclinical studies suggested that this
approach would reverse latency (89). Although a
proof-of-concept clinical study found that IL-7
caused production of virions in vivo (90), the
overall impact of the approach was an increase
in the estimated reservoir size, presumably because of proliferation and expansion of infected
cells (12). Experiments in improved preclinical
models of ART-suppressed virus infection and
proof-of-concept clinical trials will hopefully provide clarity on these and other issues.
The PrEP, PEP, and cure continuum
Treating HIV-1 with ART shortly after infection
may also contribute to HIV-1 eradication. ART
during acute HIV-1 infection reduces the size of
the reservoir (91, 92), limits the generation of escape mutants, and preserves immune function.
For these reasons, it is thought that HIV-1–infected
individuals who initiate ART during acute infection have the best chance for HIV-1 eradication,
although this group represents only a small fraction of total HIV-1–infected individuals. It is also
possible that very early ART may even be curative,
as illustrated by the case of the HIV-1–infected
infant who was started on ART at 30 hours of
life. Therapy was discontinued after 18 months,
and virus remained undetectable (through at
least month 30), suggesting that very early initiation of ART may prevent establishment of a
long-lived reservoir (28). However, the applicability of these findings to sexual HIV-1 transmission in adults remains uncertain.
The potentially curative role of ART when
administered within days of infection blurs the
traditional distinction between preexposure pro-
phylaxis (PrEP), postexposure prophylaxis (PEP),
and a cure (Fig. 3). It is well established that treat-
ing adults with ART within hours of HIV-1 ex-
posure (e.g., a needlestick injury in a healthcare
worker) substantially reduces the risk of acquir-
ing HIV-1. However, antiretroviral drugs inhibit
active virus replication in host cells, and thus the
clinical success of PEP strategies indicates that
the first HIV-1–infected cells after viral exposure
can be eradicated. Indeed, if intensive virologic
monitoring were used in these individuals, then
it is possible that some might exhibit transient
low levels of virus in blood or tissues and thus
would be considered “cured.” From this per-
spective, the use of very early ART to eradicate
HIV-1 infection may not be uncommon.
Early ART that fails to block the establish-
ment of the viral reservoir might still prevent
some of the immunologic damage that typically
occurs during acute HIV-1 infection, thus aug-
menting the capacity of the host immune system
to control viral replication. Such an ART-induced
shift toward a more effective host immune re-
sponse and a smaller viral reservoir may in rare
cases lead to sustained control of the virus (a
functional cure). Among a cohort of adults in
France who started ART during acute HIV-1 in-
fection and then discontinued therapy after sev-
eral years (the VISCONTI cohort), about 10 to
15% did not exhibit detectable viral rebound,
although replication-competent virus still per-
sisted in these individuals and they lacked pro-
tective HLA haplotypes (93). This observation
has not yet been confirmed, and the mechanism
for the posttreatment controller phenotype re-
mains to be determined. As compared with elite
controllers who naturally control HIV-1 infection
without ART, the posttreatment controllers dem-
onstrate remarkably small viral reservoirs and low
levels of T cell activation, both of which may have
contributed to the lack of rebound viremia when
therapy was discontinued.
Conclusions and perspectives
Advances over the past several years have sug-
gested that HIV-1 might be eradicated or controlled
under specific conditions. Thus, the increasing
enthusiasm for HIV-1 eradication research and
the growing public and private investment in
the HIV-1 cure agenda are justifiable. However,
as described in detail elsewhere (94, 95), major
scientific challenges remain. A more detailed
understanding of the biology of the latent viral
reservoir and the partially effective virus-specific
immune responses is critical. As the Boston pa-
tients demonstrate, improved assays are needed
to quantify the viral reservoir, and predictive
biomarkers for viral rebound are also needed.
Reliable and predictive animal models should
also be developed to evaluate concepts and to
inform clinical research strategies.
The establishment and maintenance of the
viral reservoir appears to be affected at least in
part by the immune system. Immunotherapy
approaches will therefore likely have an increasing role in HIV-1 eradication strategies in the
future. However, the optimal strategies to stimulate viral release from latency, to augment host
immune responses, and to limit negative inflammatory responses remain to be determined. Although a small number of case reports suggest
that it might be possible to eradicate HIV-1 infection in unusual circumstances, no proof of concept yet exists that chronic HIV-1 infection can
be cured by a safe and scalable intervention.
Over the next few years, multiple novel and
promising HIV-1 eradication concepts will be
evaluated. It is likely that progress will be steady
but unpredictable, and reaching the final goal
may take many years. Regardless, substantial
expansion of rigorous basic research, preclinical
studies, and clinical trials in this field will undoubtedly lead to important advances in our
understanding of the biology of the HIV-1 reservoir and the challenges that face HIV-1 eradication strategies.
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Fig. 3. PrEP/PEP/cure continuum. ART initiated before exposure is termed preexposure prophylaxis (PrEP), whereas ART initiated shortly after exposure is
postexposure prophylaxis (PEP) and forms a continuum with efforts aimed at virus eradication (cure). Even if early ART is not curative, it may reduce the size of
the viral reservoir and preserve immune function.