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Short-term pIFN-α2a treatment does not significantly reduce the viral reservoir of SIV-infected, ART-treated rhesus macaques

ABSTRACT: Objective: To evaluate the effect of short-term type I IFN treatment on the latent viral reservoir in SIV-infected rhesus macaques on ART; Methods: We infected twelve RMs intrarectally with 10,000 TCID of SIVmac239. After 6 weeks of infection, all RMs started a three-class, four-drug ART regimen. Once viral loads were consistently undetectable, six animals were administered 1 dose of pegylated IFN-α2a per week for 4 weeks with each weekly intramuscular application being 6 µg/kg.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE114561 | GEO | 2018/05/17

REPOSITORIES: GEO

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Project description:In study NCT00594880, we successfully administered weekly doses of pegylated interferon-α-2a (Peg-IFN-α2a) with antiretroviral therapy (ART) for 5 weeks, before continued Peg-IFN-α2a monotherapy to 12 weeks (primary endpoint) in chronic HIV-infected subjects. Subjects maintaining HIV viral load <400 copies/ml by primary endpoint were defined as responders. We now describe innate immune correlates and transcriptional profiles associated with viral control and decrease in integrated HIV DNA after Peg-IFN-α2a immunotherapy. Peripheral blood samples were obtained prior to Peg-IFN-α2a administration (ART), after 5 weeks of ART+Peg-IFN-α2a dual treatment, and after 12 weeks of Peg-IFN-α2a monotherapy. Cell subset modulation, natural killer cell (NK) function and signaling, as well as inflammatory mediators and gene expression were assessed. Results were analyzed using R.2.5.1 or MATLAB 7.10.0. Five weeks of ART+Peg-IFN-α2a preserved the frequency of immune subsets and NK cytotoxicity, while increased the levels of inflammatory mediators, and decreased cell-responsiveness to in vitro IFN-α re-stimulation. Gene expression analysis showed that induction of host restriction factors after ART+Peg-IFN-α2a was not solely predictive of a virologic response, and revealed a 108 gene signature that identified subjects who did not modulate genes after ART+Peg-IFN-α2a. A 29 gene signature along with higher NK cell activation and IFN-γ-induced protein 10 (IP-10) levels on ART, as well as higher in vitro responses to IFN-γ-induced NK cytotoxicity, and decrease in the frequency of NK bearing inhibitory receptors [i.e. killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 1 (KIR2DL1) or KIR2DL2/DL3] and C-C chemokine receptor type 7+ (CCR7) myeloid dendritic cells after ART+Peg-IFN-α2a distinguished responders from non-responders. Reductions in integrated HIV DNA after immunotherapy were associated with expression patterns of genes that are associated with activated cell-mediated response and NK cytotoxicity. In summary, innate activation and NK cell cytotoxicity are identified as correlates of HIV control and reduction after Peg-IFN-α2a immunotherapy in ART-suppressed subjects.

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Short-term pIFN-α2a treatment does not significantly reduce the viral reservoir of SIV-infected, ART-treated rhesus macaques

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