Type I interferons (IFN-I) are critical for controlling virus infections, but their persistent expression also contributes to impaired host immunity and virus persistence. Although IFN-I inhibit HIV-1 replication in vitro and in vivo, persistent IFN-I induction is correlated with immune dysfunction and disease progression in HIV-1 infected patients and in SIV infected monkeys. Moreover, despite efficient suppression of HIV-1 replication with combined antiretroviral therapy (cART), low levels of IFN-I signaling persist in some individuals, which may impede immune recovery and foster viral persistence.
We developed a monoclonal antibody to human IFN-α/β receptor (α-IFNAR) which can block IFN-I signaling in vivo. Humanized mice with persistent HIV-1 infection were treated with cART and IFNAR blockade Ab or isotype control (and human CD8 depleting mAb). At termination, T cell phenotype (expression of activation marker CD38 and HLA-DR, exhaustion marker PD-1, TIM3) was detected by FACS. T cell function was detected by ex vivo HIV-1 Gag peptide pool stimulation followed with IL-2/IFN-γ/TNF-α intracellular staining. Transcriptome analyses by RNA-seq were performed with purified human CD8 T cells to identify pathways and genes contributing to IFN-I-induced T cell dysfunction. To measure HIV-1 reservoir, we detect cell-associated HIV-1 DNA and RNA by PCR, and replication-competent HIV-1 by the quantitative virus outgrowth assay(QVOA). In addition, we measured virus rebound after cART discontinuation.
In HIV-infected humanized mice with cART, IFNAR blockade reduces the level of T cell activation (expression of CD38 and HLA-DR), reverses T cell exhaustion (expression of PD-1 and TIM-3). Transcriptome analysis by RNA-seq with purified CD8 T cells also indicated that IFNAR blockade reduced the expression of ISGs and genes involved in immune activation, exhaustion and cell death. We also found that IFNAR blockade rescued anti–HIV-1 T cells response. Most strikingly, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. Finally, we found that CD8 T cells rescued by IFNAR blockade were essential for HIV-1 reservoir reduction.
We conclude that low levels of IFN-I signaling contribute to HIV-1–specific CD8 T cell dysfunction and foster HIV-1 persistence in cART treated hosts.