Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection

Granulocytes are a category of white blood cells (WBCs) characterized by the presence of lobulated nuclei and secretory granules in their cytoplasm. Blood-circulating granulocytes comprise mainly neutrophils, basophils, and eosinophils. Neutrophils make up the majority (50% to 60%) of circulating WBCs; basophils constitute only 0.5% to 1% and eosinophils less than 6%. Granulocytes are differentiated from bone marrow hematopoietic stem cells; they normally circulate in the bloodstream and are recruited to peripheral tissue under certain pathological conditions (1-5). Granulocytes participate in various inflammatory reactions. Basophils and eosinophils are known to modulate allergic disorders and autoimmune diseases (6-11).Granulocytes play crucial roles in combating invading pathogens. The expression by human granulocytes of a broad range of pattern recognition receptors suggests that they play a role in various forms of host innate immunity (12-14), and evidence is mounting that granulocytes are essential to the regulation of host adaptive immunity (6,15,16). Activated granulocytes release various intracellular granule proteins or cytokines to suppress or directly kill invading microbes and parasites (17)(18)(19)(20)(21)(22)(23)(24) or to recruit other host immune cells to combat pathogens. Neutrophils are "professional" phagocytes that rapidly engulf and degrade invaders or form extracellular traps to kill extracellular pathogens (23). Eosinophils have been described as capable of modulating the functions of other immune cells (16,25).The interplays between granulocytes and HIV-1 and their contribution to HIV-1 disease progression remain elusive. The majority of peripheral blood neutrophils do not express CD4 molecules on their surface. Previous work showed that 4 of 51 (7.8%) HIV-1-infected individuals and 3 of 25 (12%) uninfected individuals had CD4 expression on their peripheral blood neutrophils

Section: Discussionmentioning

confidence: 99%

Human Blood-Circulating Basophils Capture HIV-1 and Mediate Viraltrans-Infection of CD4⁺T Cells

Jiang

Guo

et al. 2015

“…The administration of an anti-␣4␤7 monoclonal antibody reduced mucosal transmission of simian immunodeficiency virus (SIV) in macaques (43). Further studies and confirmation of the potential role of viral attachment factors in viral capture and transmission might be helpful in the design of antiviral strategies.…”

Section: Discussionmentioning

confidence: 99%

Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral trans -Infection of CD4 ⁺ T Cells

Jiang

Wei

et al. 2016

Despite great advances in antiretroviral therapies, human immunodeficiency virus type 1 (HIV-1) infection still remains a major global epidemic. Sexual transmission is the principal route of HIV-1 acquisition, making the genital and rectal mucosae the major sites of viral transmission. The intestinal mucosa is also the primary site where HIV-1 amplifies to disseminate virus throughout the host and is critical in the early events in the establishment of infection and evasion of immune defenses. However, the mechanisms contributing to the establishment of HIV-1 primary infection remain largely unexplored. Cell-associated viral dissemination has been proposed to play pivotal roles in HIV-1 primary infection, and multiple cell types, such as dendritic cells (DCs) and macrophages, have been reported to be hijacked by HIV-1 for local and systemic viral spread (1-4). DCs provide one of the best-described cell models for understanding cell-mediated HIV-1 capture and dissemination (1,(5)(6)(7)(8).Mast cells are derived from hematopoietic progenitor cells and undergo final maturation in vascularized tissues. Mast cells are strategically in close contact with the host-environment interface, such as the skin, airway, gastrointestinal tract, and urinary tract. They express numerous pathogen-associated molecular patterns and play an important role in the early immunosurveillance for many pathogens (9, 10). Mast cells can interact with various immune cells in complex ways, including release of soluble factors and direct contact (11), and are important immune effector and modulatory cells that help to link innate and adaptive immunity in the fight against pathogens (9,(12)(13)(14). They have been shown to be important for host defense against various viruses, such as vesicular stomatitis virus, Sendai virus, hantavirus, reovirus, dengue virus, influenza virus, herpes simplex virus, and murine cytomegalovirus (15-23). Additionally, mast cells can serve as antigenpresenting cells and participate in traditional immunologic synapse formation with T cells to mediate antigen-specific T cell activation (24).

“…The missing V2 region contains a highly conserved integrin-binding motif, 179 Leu-Asp-Ile/Val 181 , which can bind the ␣4␤7 integrin, the gut mucosal homing receptor for peripheral T cells (13). Although the precise function of this motif is still being questioned (14), this region may play a potentially important role in facilitating the virion getting onto cells in order for it to get into cells, and targeting ␣4␤7 reduces mucosal transmission in an animal model (15).…”

mentioning

confidence: 99%

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

Pan

Gorny

Zolla‐Pazner

et al. 2015

114

The region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2 ZM109 -1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. IMPORTANCEData from the RV144 phase III clinical trial suggested that the presence of antibodies to the first and second variable regions (V1V2) of gp120 was associated with the modest protection afforded by the vaccine. V1V2 is a highly variable and immunogenic region of HIV-1 surface glycoprotein gp120, and structural information about this region and its antigenic landscape will be crucial in the design of an effective HIV-1 vaccine. We have determined a crystal structure of V1V2 in complex with human MAb 830A and have shown that MAb 830A recognizes a region overlapping the ␣4␤7 integrin-binding site. We also showed that V1V2 forms a 5-stranded beta barrel, an elegant structure allowing sequence variations in the strand-connecting loops while preserving a conserved core. The HIV-1 envelope (Env) glycoprotein complex, consisting of glycoproteins gp120 and gp41, mediates the virus entry into the host cell. This heterotrimer is the major target for neutralizing antibodies (Abs) induced in HIV-1-infected patients and for HIV/ AIDS vaccine development (1). Glycoprotein gp120 has five variable and five conserved regions (2); the region consisting of the first and second variable regions (V1V2) is the most diverse in both sequence and length. V1V2, including residues 126 to 196 in the HXB2 numbering scheme (3), usually has two nested disulfide bonds; the V1 disulfide bond (between cysteine residues 131 and 157) is located within the V2 disulfide bond (between residues 126 and 196) (4). The average length of V1V2 is about 80 amino acids (aa), with a possibility of large length variations mostly derived from two regions, one in the middle of V1 and the other near the C-terminal end of V2. Recent data have shown that V1V2 is locate...