Abstract
Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence.IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection is restricted to humans and some nonhuman primates (e.g., chimpanzee and gorilla). Alternative model systems based on simian immunodeficiency virus (SIV) infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1, but only limited information on early events and immune responses is available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.
Highlights
Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; most model systems for human immunodeficiency virus (HIV)-1 have been used during established infection
CD3ϩ CD4ϩ T helper cells, the main target for HIV-1 infection, as well as CD3ϩ CD8ϩ cytotoxic T cells were present at physiological frequencies, and despite their lower repopulation, both CD11bϩ macrophages and CD14ϩ monocytes were present in all major organs (Fig. 1d)
To evaluate what mechanism drives the observed peripheral and splenic production of type I and III IFN at the peak of innate immune activation, prior to the HIV-1associated depletion of CD4 T cells or macrophages (Fig. 4a and d), we evaluated the presence of pattern recognition receptors (PRR) able to sense viral RNA on peripheral as well as splenic CD4 T cells (Fig. 4b and c) and macrophages (Fig. 4e and f) 10 days following infection with HIV-1
Summary
Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; most model systems for HIV-1 have been used during established infection. The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. Peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence. Even though many IFN-stimulated genes (ISGs) with antiretroviral activity have been described [3, 23], it remains unclear to what extent these are present, induced, repressed, or evaded during HIV-1 infection in vivo
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