Page 10 Adam • Evaluation of the Humoral/Fc-mediated Immune Responses… ADCC (Antibody-dependent cellular cytotoxicity) is a process that is mediated by NK cells and IgG1/IgG3 antibodies. It is focused on the elimination of HIV-1-infected host cells (especially the Helper T-cells). Being an Fc-mediated process, ADCC makes use of two key domains on the IgG1/IgG3 antibodies. First, ADCC utilizes the Fragment Antigen-Binding (Fab) domain on the IgG Ab, which is responsible for binding an antigen’s epitope that it recognizes. Epitopes commonly recognized by ADCC-mediating Abs tend to be located on gp120 (such as the V1V2 region, V3 binding loop, or CD4 binding site) or on gp41. The other domain on the IgG Ab that’s critical is the Fragment Crystallizable (Fc) domain, which is located in the constant region of the IgG Ab and binds to the Fc-Receptor (Fc R) on the NK cell. Either when an HIV-1 particle is still attached to the surface of a Helper T-cell when attempting to enter the cell, or when HIV-1 epitopes’ peptide fragments are presented on MHC-I by an infected Helper T-cell, the Fab domain on an IgG1 or IgG3 Ab will bind to the viral epitope. Subsequently, as a NK cell passes by the infected cell, the IgG1’s (or IgG3’s) Fc domain will meet and bind to the Fc R on the surface of the NK cell. This induces the NK to degranulate, thereby releasing perforin and granzyme enzymes towards the infected cell. The perforin naturally forms holes in the plasma membrane of the infected cell, allowing granzyme enzymes into the cytoplasm of the infected cell, where they subsequently induce apoptosis of the infected cell (Su et al., 2019 & Spicer et al., 2017). ADCC, however, doesn’t work alone to combat HIV-1 infection - it’s assisted by ADCP. ADCP (antibody-dependent cellular phagocytosis) is another key Fc-mediated function. ADCP also utilizes the Fab and Fc domains on IgG1 and IgG3 Abs, though the cells that mediate this function are different. Rather than NK cells accomplishing ADCP, macrophages, neutrophils, and DCs are the cells that carry out ADCP. During this process, one of two events can occur. In the first event that can occur, ADCC-mediating Abs can bind free-floating HIV-1 viral particles via the Ab’s Fab domain (similar epitopes to the ADCC process are recognized here). If multiple similar Abs bind to one viral particle, an immune complex will form that can be, in turn, phagocytosed by a passing macrophage, PMN, or DC. Alternatively, in the second possible event, the ADCC-mediating Abs can begin coating the surface of a virally infected cell (such as when there are viral particles attached to the cell’s surface attempting entry) by binding to viral particles, or MHC-expressed viral epitope fragments, with their Fab domains. Then the Abs’ Fc domains can bind to Fc Rs on passing phagocytes, inducing those phagocytes to consume, and subsequently destroy, the virally infected cells (Su et al., 2019 & Zirui Tay et al, 2019). After explaining both ADCC and ADCP, it must be reiterated that these processes are currently presumed to be crucial to preventing and suppressing HIV-1 infection based upon past studies into the correlates of immune protection against HIV-1. Therefore, a vaccine designed to elicit these immune responses is understood to be desirable, but what type of vaccine would need to be used in order to deliver the proper antigens/immunogens to the body to elicit such immune responses and build immunological memory against HIV-1? Adenovirus 26 as a HIV-1 Vaccine Vector
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