Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART

Abstract

The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies.

Fig. 1

Study design. a Individuals’ selection flow-chart. b Overview of the viral and host characteristics considered for an association with HIV-1 reservoir size and long-term dynamics during suppressive ART. ART antiretroviral therapy, PBMC peripheral blood mononuclear cells; time of untreated infection was calculated using estimated dates of infection; time to viral suppression was the time taken for viral load to drop below 50 HIV-1 RNA copies/ml plasma; PI protease inhibitor

Fig. 2

The HIV-1 reservoir size and long-term dynamics in 1057 individuals on suppressive ART for on median 5.4 years. a Beanplot of total HIV-1 DNA levels in 1057 individuals on long-term suppressive ART at 3–4 different time points (with median 1.5, 3.5, 5.4, and 10.0 years (n = 412) after initiation of ART) and the respective sample size. The p values were calculated using paired Wilcoxon tests. The individual observations are shown as small lines (gray or black) in a one-dimensional scatter plot. Overlaid is the estimated density of the distributions (filled in pink) and the median is depicted by a black line. b Histogram of linear regression slope over the first three measurements of total HIV-1 DNA levels with median 1.5–5.4 years after initiation of ART. c Spline fitted to all log10 total HIV-1 DNA/1 million genomic equivalents showing the 95% confidence intervals in blue and sampling times after initiation of ART in years on the x-axis. Gray lines indicate median observation times for respective number of individuals; ART antiretroviral therapy

Fig. 3

Determinants of HIV-1 reservoir size and long-term dynamics. a Coefficient plot showing covariables associated with total HIV-1 DNA levels 1.5 years after initiation of ART and 95% confidence intervals. Viral load <50 HIV-1 RNA copies/ml plasma or low-level viremia refer to the time from 180 days after initiation of ART to the first HIV-1 DNA quantification. Reference was defined as viral load, plasma HIV-1 RNA below 50 copies/ml, initiation after first year of HIV-1 infection, transmission group MSM, white ethnicity and HIV-1 subtype B. b Coefficient plot showing covariables associated with the decay of total HIV-1 DNA levels and 95% confidence intervals. Corrected for initial HIV-1 DNA levels using a spline. Viral load <50 HIV-1 RNA copies/ml plasma or low-level viremia or viral blips refer to the time between the first and third sample, i.e., 1.5–5.4 years after initiation of ART. Baseline as in panel (a). ART antiretroviral therapy, MSM men who have sex with men, HET heterosexual, PWID people who inject drugs, transmission group other includes unknown, and transfusion; time to viral suppression refers to time taken for viral load to drop below 50 HIV-1 RNA copies/ml plasma; CD4+ cell count was measured per 200 cells/µl blood

Fig. 4

The interplay of residual viremia and HIV-1 reservoir size and long-term dynamics. a The predicted log10 total HIV-1 DNA slope conditional on the effect of all other covariables and the observed viral load (constantly < 50 HIV-1 RNA copies/ml plasma, occurrence of viral blips, or low-level viremia) within 1.5–5.4 years after initiation of ART. b The predicted log10 total HIV-1 DNA slope and 95% confidence interval conditional on the effect of all other previously included covariables and the observed mean log10 plasma HIV-1 RNA (viral blips and low-level viremia) within 1.5–5.4 years after initiation of ART is shown in green. This was calculated using the R-package margins. The result of fitting a spline as the smoothing function for mean log10 plasma HIV-1 RNA (viral blips and low-level viremia) within 1.5–5.4 years after initiation of ART while correcting for the previously included covariables is shown in red. We choose a thin plate regression spline with dimension 20 of the basis. c Conceptual figure showing the observed associations between: (i) residual viremia, (ii) the HIV-1 reservoir size 1.5 years after initiation of ART, and (iii) the decay of the HIV-1 reservoir 1.5–5.4 years after initiation of ART. Residual viremia captured both, low-level viremia and viral blips, from 1.5 to 5.4 years after initiation of ART and was thus indicated as the mean log10 HIV-1 RNA. Arrows indicate a positive effect size, i.e., an enhancing effect. The blunted arrow indicates an inhibiting effect. p values were derived using linear regression. ART antiretroviral therapy. d Two possible scenarios explaining the interplay between residual viremia and HIV-1 reservoir size and long-term dynamics