Longitudinal Measurements of Ultra-sensitive Plasma HIV RNA and Quantitative Antibody Levels in HIV-1-infected Individuals Who Naturally Maintain Viral Loads below the Limit of Conventional Detection
Hiroyu Hatano*1, E Delwart1,2, P Norris1,2, R Hoh1, M Busch1,2, J Martin1, and S Deeks1
1Univ of California, San Francisco, US and 2Blood Systems Res Inst, San Francisco, CA, US
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.
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).
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.