Abstract
HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4+ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8+ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters best predicted viral load (R2 = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.
Highlights
HIV-1 infected controllers maintain durable viral suppression without anti-retroviral therapy (ART) and have generally been defined as either having undetectable HIV-1 RNA levels using conventional assays or having low but detectable levels of viral replication below 2000 copies viral RNA/ml [1,2,3,4,5,6]
To investigate adaptive immune parameters that correlate with host control over viral replication, we recruited HIV-1 infected viremic controllers and chronically-infected non-controllers with matched absolute CD4+ T cell counts in the absence of anti-retroviral therapy (Table 1)
We utilized a multivariable analysis to identify which immune parameters on NK cells, dendritic cells and CD8+ T cells best correlated with viral control in viremic controllers and chronically infected non-controllers with matched CD4+ T cell counts in the absence of ART
Summary
HIV-1 infected controllers maintain durable viral suppression without anti-retroviral therapy (ART) and have generally been defined as either having undetectable HIV-1 RNA levels using conventional assays (elite controllers) or having low but detectable levels of viral replication below 2000 copies viral RNA/ml (viremic controllers) [1,2,3,4,5,6]. A role for the adaptive T cell response in maintaining low viral loads among controller subjects is supported by these studies, as many as half of the subjects from HIV-1 controller cohorts exhibit low to undetectable Gag-specific CD8+ T cell responses and/or lack protective MHC-I alleles [18,19] Gag-specific CD8+ T cell responses target virally infected target cells early in the viral life cycle before integration and viral replication occurs [29], and are believed to limit viral replication by targeting conserved epitopes that reduce viral fitness following the emergence of escape mutations [30,31,32,33].
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