Identification of Host Trafficking Genes Required for HIV-1 Virological Synapse Formation in Dendritic Cells.

Dendritic cells (DCs) are one of the earliest targets of HIV-1 infection acting as a "Trojan horse," concealing the virus from the innate immune system and delivering it to T cells via virological synapses (VS). To explicate how the virus is trafficked through the cell to the VS and evades degradation, a high-throughput small interfering RNA screen targeting membrane trafficking proteins was performed in monocyte-derived DCs. We identified several proteins including BIN-1 and RAB7L1 that share common roles in transport from endosomal compartments. Depletion of target proteins resulted in an accumulation of virus in intracellular compartments and significantly reduced viral trans-infection via the VS. By targeting endocytic trafficking and retromer recycling to the plasma membrane, we were able to reduce the virus's ability to accumulate at budding microdomains and the VS. Thus, we identify key genes involved in a pathway within DCs that is exploited by HIV-1 to traffic to the VS.IMPORTANCE The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4+ T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4+ T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4+ T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo.

Extracellular Adenosine Triphosphate: A Modulator of Cutaneous Candida albicans Infection.

Typically found in the skin, Candida albicans can be both commensal and pathogen. In their report, Zhang et al. (2021) address the regulation of C. albicans skin infection by extracellular adenosine triphosphate-a metabolite actively released by the fungus-that potentially modulates cutaneous infection.

Kallikrein-6-Regulated Pathways Shed Light on New Potential Targets in Varicella Zoster Virus Infection.

Varicella zoster virus, the worldwide infectious human virus responsible for acute varicella and chickenpox, commonly spreads from exposure through contact with a skin lesion or airborne respiratory droplets. Keratinocytes, major targets and source of transmission of the virus present in the skin, represent an ideal choice of cell to stop early virus progression. In their recent study, Tommasi et al. show regulatory mechanisms of cytokeratin 10 through the protease kallikrein-6 as a suitable and druggable pathway to reduce varicella zoster virus dissemination.

New Cutaneous Vaccine Adjuvant that STINGs a Little Less.

Cutaneous vaccination can be a challenge because the development of local skin inflammation is often unavoidable. Thus, it is important to identify and validate new vaccine adjuvants that enhance immunization without the burden of inflammation. Wang et al. now report on a cyclic GMP-AMP adjuvant, the natural stimulator of interferon genes agonist, providing evidence for potent immune responses without inflammation.

Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1.

Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach because of efficient antigen delivery and safety. We evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles to induce immunity against HIV-1. This peptide-conjugated polypropylene sulfide nanoparticle formulation did not accelerate the maturation of blood- or skin-derived subsets of dendritic cells, either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, dendritic cell-mediated capture of particulate antigen in this form induced potent HIV-1-specific CD4(+) T-cell responses, as well as B-cell-mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1.

Altered antigen-presenting cells during HIV-1 infection.

PURPOSE OF REVIEW: The purpose of this study is to describe the alterations that HIV-1 induces in antigen-presenting cells (APCs), in vitro, ex vivo and in vivo. RECENT FINDINGS: HIV-1 disarms several arms of the immune system including APCs. We summarize here recent findings on the impact of the virus on APC. SUMMARY: HIV-1 can invade APC and overall reduce their capacity to present antigens effectively, mostly by reducing their numbers and inducing permanent hyperactivation. This occurs via a combination of alterations; however, the host can counteract, at least in part, some of these defects via restriction factors, autophagy, the production of type I interferon, antiviral cytokines, among others. However, these specific mechanisms of viral evasion from APCs' control lead to a chronic hyperactivation of the immune system implicated in AIDS-related and non-AIDS related pathogenesis. Unfortunately, the current regimens of antiretroviral therapy are unable to dampen sufficiently APC-driven viral-induced immune hyperactivation. Understanding how HIV alters APC will help to tune appropriately both intrinsic immunity and innate immunity, as well as achieve efficient antigen presentation to the adaptive immune system, without inducing a detrimental pervasive hyperactivation of the immune system.

Gut flora antigens are not important in the maintenance of regulatory T cell heterogeneity and homeostasis.

CD25(+) regulatory T cells (Treg) are a heterogeneous population that exists as CD44(low) and CD44(high) cells. Here we report that while both CD44(low) and CD44(high) Treg are anergic and express similar levels of Foxp3, CD44(high) Treg are highly proliferative in vivo and are more potent suppressors in vitro than CD44(low) Treg. From analysis of the properties of Treg derived from germ-free mice, it was concluded that peptide antigens derived from intestinal microorganisms are not essential for the generation, in vivo proliferation or suppressive activity of Treg. Our results suggest that gut flora antigens play little or no role in the heterogeneity and homeostatic regulation of Treg.