Page 6 Adam • Evaluation of the Humoral/Fc-mediated Immune Responses… (bNAbs) can be produced in some individuals, which can neutralize a broad spectrum of HIV-1 strains (Su et al., 2019; Corti et al., 2010). Now after this brief, yet hopefully sufficient, overview of HIV-1 pathogenesis and immune response mechanisms, it would also be helpful to briefly summarize the disease progression that inevitably results from HIV-1 infection. Once HIV-1 has entered the body and begun establishing viral reservoirs, Acute HIV-1 Infection occurs. This stage can be accompanied with or without any noticeable signs/symptoms. If symptoms are present, they are usually flu-like in nature as the body begins its immune response against HIV-1. This stage also demonstrates a relatively large “viral load” (measurable amount of virus in the blood). The patient at this stage is considered contagious. The next stage of disease progression is Chronic HIV-1 Infection. Although by this stage the patient is still potentially contagious, the replication rate of HIV- 1 decreases significantly, but by this point the CD4+ immune cell populations (most noticeably the Helper T-cell populations) are decreasing - even though most patients are asymptomatic at this point. The third and final stage of disease progression is acquired immunodeficiency syndrome (AIDS). Here, the CD4+ cell count is less than 200 cells/mm^3 of blood, and the individual is increasingly susceptible to death brought on by a broad array of pathogens. For example, Mycobacterium tuberculosis is the leading cause of AIDS-related death, owing to the disruption of TB-containing granulomas within tissues like the lungs. Patients with AIDS are also less capable of combating fungal infections caused by pathogens such as Candida albicans and Cryptococcus neoformans (Vaillant & Naik, 2020). Having in mind, then, the fact that HIV-1 pathogenesis has been the focus of many research projects over the past 35+ years of the HIV-1 global pandemic, it must be asked: “Why has no prophylactic HIV-1 been developed in the decades that global society’s been aware of the virus?” Over 35 Years of Failure: Why hasn't a Prophylactic HIV-1 Vaccine been Developed Yet? There are two key answers to this previous question: 1.) the incredible genetic diversity of HIV-1 and 2.) uncertainty regarding which immune responses are responsible for combating HIV-1 infection. The influenza virus is an excellent example of a virus that scientists are struggling to create a universal vaccine against, due primarily to regular antigenic drift that is brought about by the accumulation of relatively small mutations, subsequently leading to a 12% change in genetic diversity between strains each year (Fischer et al., 2007). HIV-1 on the other hand, can demonstrate about 10% genetic variation between strains in a single infected individual and around 35% genetic variation among different HIV-1 clades. Genetic variation in the same clade alone can reach as high as 20% (Corti et al., 2010). This substantial genetic variation introduces a massive problem for vaccine developers who are attempting to immunize patients with antigens (or antigen-
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