Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy

Abstract

A subset of antiretroviral-untreated, human immunodeficiency virus (HIV)-infected individuals are able to maintain undetectable plasma HIV RNA levels in the absence of antiretroviral therapy. These "elite" controllers are of high interest as they may provide novel insights regarding host mechanisms of virus control. The degree to which these individuals have residual plasma viremia has not been well defined. We performed a longitudinal study of 46 elite controllers, defined as HIV-seropositive, antiretroviral-untreated individuals with plasma HIV RNA levels of <50 to 75 copies/ml. The median duration of HIV diagnosis was 13 years, the median baseline CD4(+) T-cell count was 753 cells/mm(3), and the median duration of follow-up was 16 months. Plasma and cellular HIV RNA levels were measured using the transcription-mediated amplification (TMA) assay (estimated limit of detection of <3.5 copies RNA/ml). A total of 1,117 TMA assays were performed (median of five time points/subject and four replicates/time point). All but one subject had detectable plasma HIV RNA on at least one time point, and 15 (33%) subjects had detectable RNA at all time points. The majority of controllers also had detectable cell-associated RNA and proviral DNA. A mixed-effect linear model showed no strong evidence of change in plasma RNA levels over time. In conclusion, the vast majority (98%) of elite controllers had measurable plasma HIV RNA, often at levels higher than that observed in antiretroviral-treated patients. This confirms the failure to eradicate the virus, even in these unique individuals who are able to reduce plasma viremia to very low levels without antiretroviral therapy.

FIG. 1.

In vitro spiking experiments showing the relationship between HIV RNA levels and S/Co ratio using the TMA assay. Each dot represents the mean of the results for four replicates (randomly selected from 20 replicates) performed by four different laboratory technicians; the lines represent the mean S/Co ratio for each viral load copy number (0, 1, 3, 10, 30, 100, and 300 copies/ml).

FIG. 2.

Plasma HIV RNA levels in elite controllers. Plasma HIV RNA levels (S/Co ratio) using the TMA assay in a subset (n = 16) of elite controllers with ≥20 months of follow-up. Each panel represents longitudinal plasma HIV RNA levels for one subject.

FIG. 3.

Baseline plasma HIV RNA level for 37 HAART-suppressed subjects and 46 elite controllers (EC). The lines represent the median S/Co ratio for each group.

FIG. 4.

(A) Association between baseline plasma HIV RNA and HIV antibody levels (n = 46; Spearman's rho = 0.43; P < 0.01). (B) Association between baseline CA-RNA and HIV antibody levels (n = 25; Spearman's rho = 0.50; P = 0.01). (C) Association between baseline proviral HIV DNA and HIV antibody levels (n = 24; Spearman's rho = 0.40; P = 0.06). Plot excludes one outlier.