Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers

Abstract

The study of HIV-infected "controllers" who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of "elite" controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov NCT01025427).

Figure 1. Change in peripheral CD4+ T cell count and rectal CD4+ T cell content.

Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point.

Figure 2. Change in ultrasensitive plasma HIV RNA and HIV antibody levels.

Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point. S/Co = signal/cutoff ratio.

Figure 3. Change in cell-associated HIV RNA and total HIV DNA in rectum.

Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point.

Figure 4. Change in integrated HIV DNA in peripheral blood.

Change in integrated DNA levels before and after 21 weeks of antiretroviral therapy was measured using the paired t-test with bias-corrected and accelerated non-parametric confidence intervals. PBMCs = peripheral blood mononuclear cells.

Figure 5. Change in T cell activation in peripheral blood.

Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point.

Figure 6. Change in T cell activation in rectum.

Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point. GALT = gut-associated lymphoid tissue.

Figure 7. Change in high sensitivity C-reactive protein.

Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point. hsCRP = high sensitivity C-reactive protein.

Figure 8. “Elite” controllers (n = 4).

Change in ultrasensitive plasma HIV RNA, HIV antibody levels, and T cell activation in peripheral blood and rectum in 4/16 controllers with baseline plasma HIV RNA <40 copies/mL. Thin lines indicate data for each individual subject (n = 4). The thick line indicates the estimated mean value over time from mixed effects linear regression for the entire cohort (n = 16). The y-axes are on the same scale as Figures 2, 5, and 6. P-values refer to change from baseline at each referenced time-point. S/Co = signal/cutoff ratio. GALT = gut-associated lymphoid tissue.