Channels • 2022 • Volume 6 • Number 2 Page 9 the funding’s of this study, that non-neutralizing Ab functions (Fc-mediated effector functions), mediated by IgG1 and IgG3, were primarily responsible for the reduction in infection risk as a result of the RV144, rather than neutralizing Ab functions (which normally play an instrumental role in combating other kinds of viral infections.) In other words, RV144 demonstrated that the goal of protective immunity can be achieved without the work of neutralizing Abs (Haynes et al., 2012; Kim et al., 2014). The RV144 trial, however, isn’t alone in suggesting the primacy of non-neutralizing, Fc-mediated effector functions in protection against (and control of) HIV-1 infection. Research prior to the RV144 trial already demonstrated that the speed at which HIV-1 disease progression occurs appears to be correlated with the concentrations of ADCC- mediated Abs observed, with those showing higher concentrations of ADCC-mediated Abs progressing much slower toward AIDS than individuals who possessed lower concentrations of ADCC mediating Abs (Baum et al., 1996). Additionally, studies in rhesus macaques, with a very similar virus to HIV-1 (called “SHIV” for Simian-human immunodeficiency virus), have demonstrated that another Fc-mediated function, known as ADCP (Antibody-Dependent Cellular Phagocytosis), not only increases in activity during successive challenges with virus but is also correlated positively with protection (Barouch et al., 2013). Furthermore, another crucial discovery that has been made concerns the nature of HIV-1-specific immune responses in people known as “elite controllers.” Elite controllers are individuals who can effectively control HIV-1 disease progression without the assistance of any antiretroviral therapy (ART). In fact, viremia in these patients is usually very low, if not completely undetectable. Both ADCC activity and Fc-mediating Ab titers have been shown to be more frequent (ADCC) and larger in concentration (Fc-mediating Abs) in Elite controllers as compared to chronically infected nonelite controllers. In fact, in one study ADCC activity was observed to be present in all (100%) of tested elite controllers, but only present in around 40% of non-elite controllers. Additionally, in the same study, ADCC-mediating Ab titers were observed to be at least 10 times higher in the elite controller participants than in the non-elite controller participants (Lambotte et al., 2009). It should be noted, however, that there remains uncertainty as to whether or not the magnitude of ADCC activity and ADCC-mediating Ab titers strictly determines how well an elite controller can suppress viremia. Intriguingly, some studies have demonstrated that elite controllers do not appear to necessarily have increased ADCC activity or higher ADCC mediating Ab titers compared to non-elite controllers. Rather, it seems as though the ability of an elite controller to suppress viremia is based more so on how well the immune system can coordinate the different Fc-mediated effector functions (like ADCC and ADCP) in a synchronized attack against HIV-1 (Ackerman et al., 2016). Since these Fc-mediated effector functions appear so critical to the immune response against HIV-1 (in particular ADCC and ADCP), it would be beneficial to briefly discuss how each of these mechanisms operate.
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