Discord controllers: characterising a new viremic controller phenotype
Muirgen Stack, HIV i-Base
The results from this study suggest more evidence for the role of immune activation in disease progression, including in the subset of patients who experience decline of CD4+ T cells yet maintain low plasma RNA-loads.
Groves and colleagues from Queen Mary’s School of Medicine and Dentistry and Barts and The London NHS Trust Department of Virology analysed a subgroup of HIV-1 viraemic controllers, which presented with both unusual immunology and clinical uncertainty (published on 16 August ahead of print in the Journal of AIDS). 
Viraemic controllers are defined as HIV positive individuals who maintain HIV suppression level without the use of ARVs. They are distinguished from normal progressors in having HIV RNA-loads below 2000 copies/ml and CD4+ T-cell counts of >450 cells/mm3 (as defined by the International HIV Controller Consortium). This review covers the complex mechanism that might explain these responses.  Therefore, the identification of a new subset of patients that seem to show a mixture of traits convergent to both viraemic controllers and progressors is extremely important in the broader context of elucidating how immunopathophysiology contributes to disease progression. 
Patients were recruited from outpatient clinics at Barts and The London and Homerton University Hospital Trusts. Of 3000 clinic attendees, 82 were identified as HIV-1 viraemic controllers, divided into 64 “typical” controllers (HIV RNA-loads below 2000 copies/ml and CD4+ T-cell counts of >450 cells/mm3) and 18 “discord” controllers (HIV RNA-loads below 2000 copies/ml and CD4+ T-cell counts of <450 cells/mm3) thus representing 2.7% and 0.6% of patients respectively. The two controller cohorts were compared against progressors (HIV RNA-loads above 10,000 copies/ml and CD4+ T-cell counts of <450 cells/mm3) and in some cases HIV negative patients.
The authors quantified CD4+/CD8+ T-cell subsets, HIV RNA-loads, HIV DNA-loads and analysed viral clade. Demographics identified in the controller cohort included age, gender and ethnicity. Of note, 13 patients (3 discord and 10 typical controllers) were treated with ART during pregnancy but controlled plasma RNA-load for at least 12 months before and after. Two other typical controllers with low RNA-loads for 3.7 and 3.5 years subsequently showed a significant rise in RNA-loads whilst maintaining good CD4+ T-cell counts (geometric means of 732 and 708 cells/mm3, respectively). All of the mentioned patients were included in the patient characteristics and clade analysis, but were not used for DNA-load and T-cell analysis.
In the controller cohort, average age was median 37.5 (IQR 32-43 years) vs 38.5 (32.5-49 years), percentage of cohort of female gender was 54.7% vs 61.1%, plasma RNA-load (log10 copies/mL) was median 408.5 (IQR 160.7-1000) vs median 428.6 (100.3-1043) and CD4+ T-cell count (cells/mm3) was median 699.3 (IQR 550.4-843.1) vs median 347.2 (298-406.6) for typical and discord controllers respectively. The only statistically significant difference between the groups was discord controllers having a lower %CD4 T-cells than typical controllers, median 22.3 (IQR 17.6-26) vs median 33.7 (IQR 23.8-40, p<0.0001).
Of the n=15 discord controllers where clade data was available, 40% were positive with subtype CRF02_AG compared to 19.5% of typical controllers. As the clade distribution of the study population was diverse (East London), any inference from this is currently unclear.
Despite an extensive T-cell subset analysis, statistical significance for comparisons between controllers, progressors and HIV negative patients is lacking. Unfortunately, this remained true for CD8+ T-cell subset populations and levels of CD4+/CD8+ T-cell activation. However, this should not wholly detract away from the researcher’s findings, as discord controllers only seem to represent a very small proportion of patients in the wider population.
Discord controllers appear to share many characteristics with progressors namely, depleted naive CD4+ T cells and increased CD4+ T cell activation levels. However, discord controllers appear to have more similarities to typical controllers than progressors in both their CD8+ T-cell activation pattern and preservation of CD8+ naïve T-cell pool.
Both discord and typical controllers had much lower plasma HIV RNA-loads than viraemic noncontrollers (p<0.0001) yet, discord controllers are then distinguished from typical controllers by having higher HIV-1 DNA loads (p=0.002).
Although more clarification on the defining features of discord controllers is needed, the identification of this subset is important for two reasons. Firstly, it provides evidence of sub-clinical disease progression despite maintaining low plasma viral load. This may be an indicator for more regular analysis of HIV DNA-loads and/or CD4+ T-cell activation levels in patients who present with a seemingly anomalous decreasing CD4+ T-cell count.
Secondly, the authors offer multiple explanations for the disease progression seen in discord controllers, with most possibilities aligning alongside the effects of aberrant immune activation/dysregulation.  Whilst these may be valid, it still remains unclear why high cellular HIV DNA levels do not result in higher-level plasma RNA viral load in discord controllers – perhaps suggestive of increased levels of ongoing replication in vivo.
Finally, a concern when characterising new subsets of patients is that it may just be a failure to account for natural variation in the population, in this case lower “normal” CD4+ T-cells counts. However, during the study five patients in the discord controller group started ART and all saw modest gains in their CD4+ T-cell counts. This should hopefully help to define discord controllers as patients who can respond well to treatment even if they appear to be somewhat managing the virus without ARVs.
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