Background
A significant percentage of PWH who start or restart antiretroviral therapy (ART) with low CD4+ counts fail to mount a robust CD4+ T cell response despite suppressive ART (suboptimal immune responders, SoIRs). A correlation between the frequency of infected CD4+ T cells and low CD4+ counts on ART has been reported. However, these studies did not control for CD4+ nadir nor time on ART, and it remains unclear whether SoIRs have a higher burden of HIV-infected CD4+ T cells.
Methods
We performed the intact proviral DNA assay (IPDA) to quantify estimated frequency of intact and defective HIV proviruses among CD4+ T cells isolated from cryopreserved samples from 62 SoIRs and 67 PWH controls at 1-4 yr post-ART initiation. All participants started/restarted ART with a CD4+ count <200 and maintained virologic suppression for 5+ years. SoIRs were defined as PWH with a CD4+ count <350 at 5 yr post-ART start, controls as PWH with a CD4+ count >500 at 5 yr post-ART start. Controls were selected to match SoIRs on age, race, sex, CD4+ nadir, hepatitis C (HCV) serostatus, ever-IV drug use, and time from ART start to sample collection. Samples and clinical data were obtained from 4 cohorts – ALLRT/ACTG (n=76), the SCOPE cohort (n=45), the Cleveland Immune Failure cohort (CLIF, n=7), and the Johns Hopkins HIV Clinical Cohort (JHHCC, n=1). The average of ~5 replicates per sample-timepoint was used. Mann Whitney U test or chi squared test were used for comparisons.
Results
Consistent with design, no significant differences were seen between SoIRs and controls by age at ART start/restart (median 45 vs 42, respectively), race, sex (10% vs 15% female sex), CD4+ nadir (median 29 vs 31), HCV seropositivity (15% each), or ever-IV drug use (21% vs 18%). The median time from ART start or restart to sample collection was 22 months in each group. The median CD4+ count 5 yr after ART start/restart was 265 among SoIRs vs 650 among controls.
There were no significant differences between SoIRs and controls in the frequency of intact or defective proviruses among circulating CD4+ T cells (Figure).
Conclusions
We demonstrate here that the frequency of HIV-infected CD4+ T cells – whether harboring intact or defective HIV proviruses – in the first few years after ART initiation does not associate with future SoIR status. Further research is needed to understand the biological contributors to poorer outcomes in SoIRs.
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