Human immunodeficiency virus type-1(HIV-1) infectionis associated with aberrant immune activation, however, most model systems for HIV-1have been used during established infection. Here, we utilizeultra-sensitive HIV-1quantification to delineate early events during the HIV-1eclipse,burstand chronicphases ofHIV-1infection in humanized mice. We show that veryearlyin infection, HIV-1suppresses peripheral type I interferon(IFN)and interferon-stimulated gene (ISG) responses,including the HIV-1restriction factorIFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1infection differentially affects peripheral and lymphoid TLR expression profiles in T cells and macrophages. This resultsin a trend towardsanaltered activation of NFkB, TBK1 and IRF3. The subsequenttype I and III IFN responsesresult in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of theHIV-1restriction factorSAMHD1returnsto levels below those observed in uninfected mice, suggesting that HIV-1interferes with their basal expression. However, peripheralcells, still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISG in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1infection and suggests that blocks to the induction of HIV-1restriction factors contribute to theestablishment of viral persistence.