Page 4 Adam • Evaluation of the Humoral/Fc-mediated Immune Responses… DC-SIGN (Dendritic Cell-specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin). Upon binding of gp120 to this receptor, HIV-1 viral particles are endocytosed into the DC and undergo MHC-I and MHC-II antigen processing (Moris et al., 2004) in order that the now activated DC may present (via cross-presentation) viral peptide fragments to both naive CD4+ Tcells and naive CD8+ T-cells in nearby lymph nodes (LNs). Although this process will allow for the activation of the Adaptive Immune system, HIV-1 viral particles can also become embedded and stuck within the numerous glycoproteins on the outside of the activated DCs. As the DCs presenting HIV-1 peptide fragments migrate to nearby LNs, HIV-1 particles can ride along on the outside of the DC, effectively hitching a ride towards vulnerable CD4+ T-cells located within the nearby LNs. Thus, once the activated DC begins presenting to naive Helper Tcells during the clonal selection process, HIV-1 viral particles come in contact with vulnerable Helper T-cells and can subsequently infect those Helper Tcells (the overall process is termed the “trans-infection pathway.”) Alternatively, DCs, - due to their own expression of CD4 - are able to be infected by HIV-1 particles (though to a lesser extent than Helper T-cells and typically only in inactivated DCs). This subsequently results in what is known as the “de novo pathway” of infection, whereby new HIV-1 particles bud out from infected DCs and infect nearby Helper T-cells in the local MALT of LNs (Cavrois et al., 2007). Therefore, to this point in the infection process, HIV-1 viral particles have made it past the mucosal barriers and have gained access to vulnerable Helper T-cells in either the MALT or the LNs. It is from here that damage to the immune system can begin and the body’s natural immune response to HIV-1 can also start. Upon exposure of Helper T-cells to HIV-1, envelope glycoprotein spikes (composed of trimers of gp120-gp41 heterodimers) bind CD4 and the coreceptor, CCR5 (or CXCR4). Which coreceptor is utilized depends on the tropism of the HIV-1 strain. Some strains are M-Tropic (utilizing CCR5), some are T-Tropic (utilize CXCR4), and others are Dual-Tropic (utilize CCR5 or CXCR4). More specifically, gp120 subunits bind first to CD4 receptors, thereby inducing aggregation of CD4 and CCR5 (or CXCR4), subsequently leading to the interaction of gp120 subunits and the coreceptor. Gp41 then aids in pulling upon the cell’s plasma membrane in order to facilitate the injection of the virus’ core into the Helper T-cell (Li & Clercq, 2016; Picchio et al., 1998). Then, once viral Reverse Transcriptase begins converting HIV-1’s RNA genome into cDNA, three different intracellular responses are possible within the Helper T-cell (or other CD4+ cell). If the Helper T-cell happens to have already been activated, whether in response to HIV-1 or another antigen, then the cDNA product of Reverse Transcription can act as a PAMP (pathogen-associated molecular pattern) to an intracellular PRR (pattern recognition receptor) known as IFI16 (interferon- inducible protein 16), which then activates a signaling cascade leading to the activation of NF B - leading to the production of Type-1 IFNs that can activate Natural Killer (NK) cells, as well as warning nearby cells and interfering with viral replication (part of the innate immune response to HIV-1) (Altfeld & Gale, 2015). What’s fascinating, however, is that if the infected Helper T-cells isn’t previously activated, such as a resting Helper T-cells in the MALT (known as “bystander” Helper T-cells), then the binding of HIV-1 cDNA to IFI16 can
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