Abstract
BackgroundHIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy. The mechanisms of suppression are incompletely understood. Modulation of HIV-1 replication by miRNAs has been reported, but the role of small RNAs in ES is unknown. Using samples from a well-characterized ES cohort, untreated viremic patients, and uninfected controls, we explored the PBMC miRNA profile and probed the relationships of miRNA expression, CD4+ T-cell counts, and viral load.ResultsmiRNA profiles, obtained using multiple acquisition, data processing, and analysis methods, distinguished ES and uninfected controls from viremic HIV-1-infected patients. For several miRNAs, however, ES and viremic patients shared similar expression patterns. Differentially expressed miRNAs included those with reported roles in HIV-1 latency (miR-29 family members, miRs -125b and -150). Others, such as miR-31 and miR-31*, had no previously reported connection with HIV-1 infection but were found here to differ significantly with uncontrolled HIV-1 replication. Correlations of miRNA expression with CD4+ T-cell count and viral load were found, and we observed that ES with low CD4+ T-cell counts had miRNA profiles more closely related to viremic patients than controls. However, expression patterns indicate that miRNA variability cannot be explained solely by CD4+ T-cell variation.ConclusionsThe intimate involvement of miRNAs in disease processes is underscored by connections of miRNA expression with the HIV disease clinical parameters of CD4 count and plasma viral load. However, miRNA profile changes are not explained completely by these variables. Significant declines of miRs-125b and -150, among others, in both ES and viremic patients indicate the persistence of host miRNA responses or ongoing effects of infection despite viral suppression by ES. We found no negative correlations with viral load in viremic patients, not even those that have been reported to silence HIV-1 in vitro, suggesting that the effects of these miRNAs are exerted in a focused, cell-type-specific manner. Finally, the observation that some ES with low CD4 counts were consistently related to viremic patients suggests that miRNAs may serve as biomarkers for risk of disease progression even in the presence of viral suppression.
Highlights
HIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy
Associations of host microRNA expression with HIV-1 elite suppression have not been described in the literature; there has been a strong focus on miRNA in cancer research and, increasingly, in investigations of infectious disease. miRNAs associated with medical conditions may serve as valuable biomarkers [5], especially when present and detectable in accessed body fluids, and clinical assays are currently under development for diagnosing and staging specific cancers or monitoring response to treatment
NanoString miRNA profiling distinguishes control and ES from viremic individuals RNA was isolated from peripheral blood mononuclear cells (PBMC) of eight uninfected individuals, seven HIV1-infected elite suppressors (ES), and seven HIV-1-positive viremic patients (Table 1), using consistent purification technique [30] and simultaneous isolation to avoid batch effects
Summary
HIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy. A minority of individuals, known as elite controllers or elite suppressors (ES), are able in the absence of antiretroviral treatment to resist progression to HIV disease and to maintain peripheral blood viral loads below the limit of detection of current clinical assays (50 copies/mL). The mechanisms whereby this control is achieved remain incompletely understood despite substantial advances in recent years in the characterization of both host and viral factors associated with elite suppression [1,2,3]. Inhibiting the action of miR-122 appears to be a viable therapeutic option [11], with an inhibitor currently in phase II trials
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