The persistence of a viral reservoir in HIV-1 infected patients under suppressive
antiviral treatment has thus far prevented achieving a functional HIV-1 cure. Crucial
in these initial strides to identify cure strategies is patient selection. Interventional
research on cure in HIV-1 patients usually aims to demonstrate at least one of the
following outcomes: a significant depletion of the inducible viral reservoir or the
stable absence of renewed viral replication as the infected patient discontinues antiviral
therapy. In this article of EBioMedicine, Gálvez et al. [1] identify a unique “LoViRet”
patient category with an exceptionally low viral reservoir under c-ART, despite starting
therapy during the chronic phase of the disease. So how do the different parameters
to assess the success of investigational HIV-1 cure strategies apply to LoViRet patients
and how can we harness these insights into meaningful interventional studies?
First, the presence of a small inducible latent viral reservoir that can be therapeutically
targeted, as present in LoViRet patients, is likely essential for current pilot studies
that aim to demonstrate the possibility of an antiretroviral drug-free life in patients
with chronic HIV-1 infections. One of the promising strategies studied over the last
decade to achieve HIV-1 cure addresses the caveat that latent HIV-infected cells remain
invisible to antiviral host responses. By pharmacologically triggering HIV-1 gene
expression through so-called latency reversing agents (LRA), we can reverse latency
[2,9]. Hope is then put on elimination of reactivated cells via (drug-boosted) viral
cytopathic or intrinsic host cell pro-apoptotic mechanisms or via extracellular immune
effector cell-based clearance [3,9]. Hence, the presence of a small limited reservoir
in LoViRet patients is likely beneficial to achieve significant reservoir elimination
via curative intervention strategies.
Secondly, a competent immune compartment is key to eliminate residual reservoir cells.
Because chronically infected individuals generally present an impaired immune compartment,
harnessing potent HIV-1 specific CD8+ T cells has posed a major challenge to past
eradication trials. Thus, to achieve efficient elimination of HIV-1 infected cells,
latency reversal would ideally be combined with approaches that effectively trigger
mechanisms of killing by enhancing extrinsic immune-based clearance or inducing intrinsic
cell death [4,5]. LoViRet patients described by Gálvez et al., while chronically HIV-1
infected, have a remarkably low viral reservoir together with an overall preserved
immune compartment. Notably, these exceptional characteristics are generally found
in HIV-1 controllers and patients who initiate c-ART in the acute stage of the infection
[6,7]. Gálvez et al. observed a direct correlation between low HIV-1 DNA levels in
LoViRet individuals and a preserved CD8+ T cell compartment before treatment and higher
proportion of naïve CD8+ T cells after treatment initiation. Such traits hint towards
a less impaired immune system and likely better cytotoxic responses before and after
c-ART, that could potentially prevent a massive reservoir seeding. In context of reservoir
depletion studies that center on viral reactivation and clearance, selection of patient
cohorts with not only a lower reservoir threshold but also an intrinsically preserved
cytotoxic cellular immunity compartment is thus likely crucial to reach an effective
elimination of HIV-1 infected cells.
Another striking observation, described by Gálvez et al., is that CD8+ T cells from
LoViRet individuals do not show enhanced antiviral inhibition activity or a less immune
exhausted phenotype when compared to controls, despite having low levels of circulating
HIV-1 antigen. This seems to be different from CD8+ T cells from HIV controllers [6]
and hints towards a different mechanism driving the low reservoir size observed in
LoViRet. Assessing the relevance of the specific CD8+ T cell diversity and functionality
in these patients is crucial to infer causality and, because the immune system is
certainly not the only factor influencing reservoir size, further investigation into
the intrinsic host factors (e.g. neutralizing antibodies, restriction factors or antibody-dependent
cellular cytotoxicity) and viral characteristics is needed to unveil the mechanisms
behind the specific reservoir dynamics observed in LoViRet individuals.
Thus, additional characterization and insights into the kinetics of the inducible
reservoir in this patient population is needed to put in perspective a potential role
for LoViRet patients in reservoir eradication studies. Here, future studies will have
to deal with assay sensitivity issues necessitating high input numbers of cells, which
limits applicability. In smaller reservoirs, it will be increasingly difficult to
detect relevant reservoir decay during interventional studies, or to determine the
point at which c-ART can be safely stopped. Also of importance, in context of immune-mediated
clearance, assessing the specificity and avidity of cytotoxic responses is essential
to ensure an efficient elimination of reactivated cells [8]. Lastly, it is important
to note that the far majority of people are diagnosed and treated during chronic phases
of HIV-1. Of these, only a small minority will hold a LoViRet phenotype, estimated
at 6% based on the current paper. Although non-LoViRet patients have a more unfavorable
starting position in terms of reservoir size, the effect of any intervention on the
inducible reservoir decay and its predictive biomarkers can be better studied. On
the other hand, the distinguished immune features of LoViRet individuals and their
correlation to reservoir dynamics accentuate their added value for customized patient
cohorts in HIV-1 cure studies. Patient stratification by LoViRet state could therefore
be very beneficial and serve both aspects of cure research: optimal reservoir decay
study together with obtaining a functional cure.
All in all, the study presented by Gálvez et al. investigates for the first time the
reservoir dynamics and immune characteristics of chronic patients with a very low
level of HIV-1 DNA. Although the relevance of this cohort in future cure studies is
yet to be assessed, the heterogeneity of HIV-1 patients who started c-ART during chronic
infection supports using stratification by LoViRet status to identify patients in
whom curative interventions is most realistic towards a c-ART-free life.
Authors’ contribution
Raquel Crespo performed the literature search and the writing. Casper Rokx and Tokameh
Mahmoudi performed the writing.
Declaration of Competing Interest
Dr. Rokx reports grants and other from Gilead Sciences, grants and other from GSK,
grants and other from Janssen-Cilag, grants from MERCK, grants from Dutch Federation
Medical Specialists, outside the submitted work. Dr. Mahmoudi reports grants from
Gilead Sciences, grants from ViiV Healthcare, non-financial support from First health
Pharma, outside the submitted work; In addition, Dr. Mahmoudi has an International
Patent Application Serial No. PCT/US19/41466 pending. Dr Crespo has nothing to disclose.