Type I IFN responses in rhesus macaques prevent SIV transmission and slow disease progression

In acute HIV infection immune activation may provide target cells and drive virus replication, which innate immunity may limit. Thus, the net effects of inflammatory mediators, including type I interferon (IFN-I), are unclear. Here, we block IFN-I signaling during pathogenic acute SIV infection with an IFN-I receptor antagonist. Delayed antiviral gene expression, increased SIV reservoir, increased CD4 T cell depletion and accelerated progression to AIDS and death ensue despite decreased T cell activation. In contrast, IFNa2a treatment initially upregulates antiviral genes and prevents systemic SIV infection after rectal challenge. Antiviral gene expression normalizes, and infection ensues with fewer transmitted/founder variants. Continued IFNa2a treatment causes delayed antiviral gene expression, increased SIV reservoir and increased CCR5+ CD4 T cell loss. Thus, the precise timing of antiviral gene expression has a profound impact on disease course. The benefits of early antiviral activity outweigh the harms of increased immune activation in acute SIV infection.