title: HIV persistence during antiretroviral therapy: Characteristics of residual HIV-1 RNA in plasma
Creators: name: Tsakiroglou, Maria
Publisher: name: University of Liverpool Repository
Year: 2021

description: Anti-retroviral therapy (ART) is highly effective in suppressing human immunodeficiency virus (HIV) and restoring immunocompetence. However, residual levels of HIV-1 RNA persist in patients with consistent viral suppression (viral load &lt;50 copies/mL) and some immune functions are not reversed. Characterisation of residual viraemia (HIV-1 RNA &lt;10 copies/mL) will facilitate to understand HIV persistence. A systematic review of literature was conducted to identify predictors of low level viraemia (HIV-1 RNA = 10-200 copies/mL) in patients on successful ART. To investigate factors associated with residual viraemia, we recruited a cohort of stably treated patients on first line ART with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) based regimen and no evidence of virological failure. We measured HIV-1 RNA in plasma with our in-house single copy assay (SCA) and we studied total HIV-1 DNA in peripheral blood mononuclear cells (PBMC) and PD1 expression on memory CD4 and CD8 T populations. A subset of our study cohort was sampled twice during consecutive routine visits at the HIV clinic to perform a longitudinal analysis of HIV-1 RNA in plasma, total HIV-1 DNA in PBMC and drug levels. Residual viraemia was identified in over one third (35.9%, n=19 of N=53) of subjects with a median of 3 copies/mL. In the longitudinal cohort (n=32), HIV-1 RNA presence in plasma was reproducible within an interval period of 4 months with 53% (n=17) having undetectable HIV-1 RNA at both time points and 25% (n=8) experiencing consistently detectable HIV-1 RNA. Total HIV-1 DNA in PBMC was strongly associated with residual viraemia (OR: 3.42, 95% CI: 1.32-8.83, p=0.011) in our study population. In the systematic review, low level viraemia was also associated with markers reflecting a bigger cellular reservoir including higher pre-ART viral load, total HIV-1 DNA in PBMC and shorter ART duration. Moreover, low level viraemia was more frequent with reduced adherence and with PI-based ART. The same trends were also seen in our cohort, but the number of patients on PI-based regimens (n=11) and with sub-optimal efavirenz levels (n=6) were small to allow statistical comparisons. Microbial translocation and immune activation were associated with low level viraemia in the review. On the contrary, our patients with undetectable HIV-1 RNA had higher PD1 expression on effector memory CD4 cells (median 43.9% vs. 33.7%, p=0.028), effector memory CD8 cells (median 37.5% vs. 23%, p=0.022) and central memory CD8 cells (median 24.9% vs. 15.7%, p=0.034) compared to those with detectable HIV-1 RNA. Our findings suggest that residual viraemia is probably clonal in our cohort of patients deriving mainly during activation of latently infected cells, which causes bursts of virus production. We noted that common factors were associated with both residual and low level viraemia. Although we consider residual and low level viraemia as two different entities, their sources may overlap. In this context, ongoing viral replication may drive residual viraemia in a small subset of patients. We also made an interesting observation as to PD1 expression on memory CD4 and CD8 subsets which warrants further investigation.