Editorial: Is HIV‐1 induction of macrophage expression of PD‐L1 and PD‐L2 its weakest or strongest link to disease? HIV‐1 plays both sides by augmenting and limiting T cell activation to survive in vivo

For a long time, discussions about how best to control HIV-1 disease progression have called for halting HIV-mediated immune activation, as this is considered to be a driving force of viral replication, resulting in added viral targets and eventual immune decay. If HIV-1 infection only led to activation, we would expect that infection would unrelentlessly amplify itself toward a very short disease course, as activation would likely overwhelm antiviral responses and ultimately the host. However, we know that HIV-1 viremia can be sustained without overt symptoms for many years in vivo. The recent paper by Rodrı́guez-Garcı́a et al. [1] expands a developing understanding of how HIV-1 infection may orchestrate control against immune activation by shutting down rather than promoting T cell responses via modulation of monocytes/macrophages. What would the virus gain by sacrificing T cell activation and the resulting viral replication? The establishment of an anti-T cell activation signal on long-lived macrophages would counter antiviral CD8 responses that arise throughout infection and at the same time, act to provide a “viral friendly” environment for reservoir formation in macrophages and latent CD4 populations, as these cells are also receptive to negative signals. The balance between HIV infection and immune activation has been a central focus of immunological research to better understand and eventually elicit the control of HIV infection in vivo. Although seminal works have established that CD8 T cells can elicit a powerful control of HIV infection and replication, natural history studies have also documented that CD8 responses can control the magnitude of virus but cannot mediate total clearance. Lack of eradication is proposed to be the result of multiple persistence mechanisms including the intrinsic capacity for immune escape via RTmediated epitope changes and the existence of viral reservoirs [2]. We now must add early induction of PD-1 ligands to its arsenal. The enrichment of HIV-1-specific CD8 T cells in infected persons bearing changes consistent with immune exhaustion, such as PD-1 up-regulation, has raised the idea that HIV-1 evades T cell control by driving this compartment toward nonresponsiveness [3]. Negative regulatory molecules such as PD-1 have been identified as mediators of this T cell shutdown [4 – 6]. Would the early induction of PD-L1 ensure exhaustion phenotypes earlier than otherwise achieved by sustained CD8 T cell responses? The article by Rodrı́guezGarcı́a et al. [1] advances the hypothesis that the monocyte/macrophage, by its interaction with HIV-1 and up-regulation of PD-L1/L2, is a central player in the shutdown of T cell response via PD-1 on lymphocytes (Fig. 1A). This work follows the observations of Said et al. [7], who recently proposed that viral replication in vivo can promote PD-1 expression on monocytes, which when binding with monocyte PD-L1, can induce high levels of IL-10. Novel contributions by Rodrı́guez-Garcı́a et al. [1] include the description of PD-L1 and PD-L2 expression in a human MDM system in response to HIV-1, microbial translocation production, and IL-10. They found that LPS led to an increase in PD-L1 levels from a low baseline and a minor increase in PD-L2 expression from a much higher baseline. Furthermore, inactivated HIV-1 particles increased PD-L1 and PD-L2 expression. A key, novel finding was different regulation of the two ligands by IL-10. Specifically, IL-10 increased PD-L1 expression in the presence and absence of