Channels • 2022 • Volume 6 • Number 2 Page 5 cause the activation of the inflammasome protein complex. The inflammasome complex then activates caspase-1 enzymes to mediate pyroptosis of the resting Helper T-cell. Infact, it has been suggested that the mass-suicide of many bystanders Helper Tcells is the primary driving force of disease progression to AIDS (Doitsh & Greene, 2016). This suicide, however, doesn’t occur in all resting Helper T-cells that are infected. Recognition of viral cDNA by IFI16 appears to occur only when there is incomplete reverse transcription or when there are mutations in the viral genome that result in disruptions in HIV-1 capsid (Altfeld & Gale, 2015; Doitsh & Greene, 2016). In cases where viral cDNA goes undetected then, the cDNA can be incorporated into the host cell’s genome, thereby leading to the establishment of “viral reservoirs” that can produce new viral particles once the host cell is eventually activated in the future (host cell activation, in fact, is what allows the HIV-1 to maintain and increase in population within a host (Siliciano & Greene, 2011). After partially discussing the complex innate immune response to HIV-1 infection (a topic that will be revisited shortly), as well as the primary means by which Helper T-cells population diminish during HIV-1 infection, it makes sense to go on to briefly discuss the adaptive immune response to HIV-1 infection. Once DCs have internalized HIV-1 particles and processed them via the MHC-I or MHC-II pathway (as discussed previously), the DCs present HIV-1 peptide fragments to naive T- cells. Once clonal selection and clonal activation of HIV-1-specific Helper and Cytotoxic T- cells occurs, effector T-cells begin their futile attempts to begin combating the spread of the HIV-1 infection. Effector cytotoxic T-cells (CTLs) function similarly to HIV-1 as they do in response to other viral infections. They seek out infected cells (CD4+ leukocytes) that display HIV-1 viral peptides (ones that the particular CTL clone recognizes) being presented on MHC-1 complexes and induce apoptosis of the infected cells. This process is also partially responsible for the overall depletion of Helper T-cell populations (Mohan et al., 2014). Effector Helper T-cells, on the other hand, function primarily in order to help activate HIV-1-recognizing B-cells - which have themselves encountered, endocytosed, processed, and begun presenting HIV-1 peptide fragments on MHCII themselves - that, in turn, produce antibodies against HIV-1 (most notably IgGs and IgAs). Although these Abs can operate to neutralize the HIV-1 particles, as will be discussed in greater detail later, it appears that it is actually non-neutralizing (Fc-mediating), polyfunctional Abs that have the greatest effect in combating HIV-1 infection (Rappocciolo et al., 2006; Su et al., 2019). In past studies on the progression of the humoral response to HIV-1, it appears that non- neutralizing polyfunctional Abs specific to epitopes on gp120 and gp41 are produced first (IgG1s and IgG3s facilitating Fc-mediated effector functions), followed by neutralizing antibodies (NAbs) that are effective in neutralizing the specific strains of HIV-1 that they recognize; though they inevitably struggle to keep up with the constant antigenic drift that continually occurs due to rapidly accumulating mutations, resulting in frequent appearances of “escape variants” that can go undetected by the host’s immune response until another primary response capable of recognizing the escape variants can be mounted. Finally, after anywhere from 2-5 years post infection, broadly neutralizing antibodies
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