Exploring the potential of organic compounds as antiviral agents against HIV-1 Público
Cho, Young-Jae (Spring 2021)
Abstract
Human immunodeficiency virus type 1 (HIV-1) is a member of the Lentivirus genus classified under the Retroviridae family. It was initially suggested to have been introduced into the human population via zoonotic transmission of primate lentiviruses. HIV-1 targets CD4+ T-cells, dendritic cells, and macrophages, which, if left untreated, progresses into acquired immunodeficiency syndrome (AIDS). Currently, HIV-1 viral loads are controlled using highly active antiretroviral therapy (HAART), a combination of three drugs of two or more differing origins. HAART has been crucial in suppressing HIV-1 to levels that are undetectable in some treated patients. However, an increase in the use of HAART to control HIV-1 infection, mutations in the viral enzymes due to replication errors, and the ability of the virus to rapidly replicate within the host have facilitated the emergence of viral strains that are resistant to drugs currently used in HAART. Therefore, there is a need to develop novel anti-HIV-1 agents to combat emerging resistant strains of HIV-1. In this study, we aim to identify organic compounds and mixtures of organic compounds with great inhibitory potencies against HIV-1 while exhibiting low cytotoxicity in a human T-cell line (CEMx174). A total of 35 organic compounds and mixtures were screened for cytotoxicity in an MTS assay using CEMx174 cells and screened for HIV-1 antiviral potencies using CEMx174 cells infected with HIV-1-D3-GFP vector. Out of the 35 compounds and mixtures screened, only one mixture, BK 91, exhibited both high cell viability relative to cell control (102.7%) and significant reduction in percent GFP expression (55.65±1.10, p<0.05) relative to virus control, which indicated significant viral suppression. Subsequent in-depth analysis of BK 91 determined the mixture’s CC50 (≈57.47 µg/mL) and EC50 range (between 6.5 μg/mL and 8.5 μg/mL). Further study is needed to isolate and analyze the individual compounds that comprise BK 91 to determine which components contribute to its anti-HIV-1 activity, as well as comparing the characteristics of BK 91 to HAART drugs currently used.
Table of Contents
Introduction…………………………………………………………………………………....1
Origin and Global Impact of HIV-1…………………………………………………........1
Clinical Definition of HIV/AIDS…………………………………………...….……........2
HIV-1 Structure, Transmission, and Replication Cycle…………………….............3
Highly Active Antiretroviral Therapy (HAART)………………………………............5
Protease Inhibitors…………………………………………………….…….....................5
Nucleoside Reverse Transcriptase Inhibitors...................................................8
Non-nucleoside Reverse Transcriptase Inhibitors............................................10
Integrase Inhibitors......................................................................................11
HIV-1 Resistance to HAART...........................................................................13
HIV-1 Lentiviral Vectors................................................................................14
Study Overview.............................................................................................15
Materials and Methods...................................................................................15
Cells.............................................................................................................15
BK Compounds..............................................................................................16
pD3HIV-1-GFP Vector Preparation..................................................................16
Cytotoxicity Assay..........................................................................................17
Anti-HIV-1-D3-GFP Screening........................................................................17
Determination of CC50 for BK 91.....................................................................18
Determination of EC50 for BK 91.....................................................................19 Results..........................................................................................................19 Discussion.....................................................................................................20
Tables and Figures..........................................................................................21
Table 1. Summary of compounds tested............................................................21
Figure 1. Results from cytotoxicity MTS assay...................................................24
Figure 2. Results from HIV-1 antiviral assay (BK 71 to BK 80).............................25
Figure 3. Results from HIV-1 antiviral assay (BK 81 to BK 92).............................26
Figure 4. Results from HIV-1 antiviral assay (BK 93 to BK 107)...........................27
Figure 5. Results from determination of CC50 for BK 91....................................28
Figure 6. Results from determination of EC50 for BK 91....................................29 Appendix......................................................................................................30 References....................................................................................................31
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