Background:  HIV-antibody-positive individuals (elite controllers) who maintain plasma HIV RNA levels below the limit of conventional detection in the absence of ART should provide insights into novel mechanisms of viral control. The degree to which virus is replicating in these individuals has not been well defined. 

Methods:  The isothermal transcription mediated amplification (TMA) assay was used to obtain longitudinal measurements of plasma HIV RNA in HIV controllers from the SCOPE cohort, defined as persons who are:  HIV antibody-positive, used no ART in the preceding 24 months, and had plasma HIV-1 RNA levels <75 copies/mL. The sensitivity of the TMA assay is approximately 3 RNA copies/mL when 4 replicates are performed. “Detuned” or less-sensitive enzyme immunoassay (LS-EIA) was used to obtain quantitative HIV antibody levels (measured as standardized optical density [SOD]) over time. 

Results:  Of 46 controllers examined, 39% were women, median duration of HIV infection was 13 years, and the first available CD4⁺ T cell count was 753 cells/mm³. Controllers were observed for a median 16 months and had a total of 1117 TMA assays performed on 311 specimens (median 4 replicates per specimen). Of 46 subjects, 14 (30%) had all TMA assays positive (signal:cutoff [S/Co] value >1). Only 1 subject had all TMA assays negative across all available (n = 5) specimens, spanning a period longer than 1 year. A repeated measures analysis showed an average of 0.08 increase in S/Co per month (p = 0.08). A total of 249 LS-EIA were performed on the same 46 controllers (median 4 specimens per subject). The median SOD was 4.5, which was higher than that observed in untreated individuals (n = 543, median SOD = 3.7, p = 0.03). Of 46 subjects, 2 had all LS-EIA negative (SOD <0.2), 1 of whom was the same subject who had all TMA assays negative; all LS-EIA-negative specimens were positive by standard EIA. Repeated measures analyses showed no strong evidence of change in SOD over time (an average of 0.01 increase in SOD per month, p = 0.40). There was a positive relationship between baseline TMA and LS-EIA (Spearman’s ρ = 0.43, p = 0.0025).

Conclusions:  The vast majority (98%) of elite controllers have measurable plasma HIV RNA, albeit at very low levels. This suggests the presence of replication-competent virus and a failure to eradicate the virus, even in these rare individuals who appear to be able to control the virus without ART.