{Reference Type}: Journal Article {Title}: The Impact of Drugs and Substance Abuse on Viral Pathogenesis-A South African Perspective. {Author}: Ratshisusu L;Simani OE;Blackard JT;Selabe SG; {Journal}: Viruses {Volume}: 16 {Issue}: 6 {Year}: 2024 Jun 17 {Factor}: 5.818 {DOI}: 10.3390/v16060971 {Abstract}: Illicit drug and alcohol abuse have significant negative consequences for individuals who inject drugs/use drugs (PWID/UDs), including decreased immune system function and increased viral pathogenesis. PWID/UDs are at high risk of contracting or transmitting viral illnesses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). In South Africa, a dangerous drug-taking method known as "Bluetoothing" has emerged among nyaope users, whereby the users of this drug, after injecting, withdraw blood from their veins and then reinject it into another user. Hence, the transmission of blood-borne viruses (BBVs) is exacerbated by this "Bluetooth" practice among nyaope users. Moreover, several substances of abuse promote HIV, HBV, and HCV replication. With a specific focus on the nyaope drug, viral replication, and transmission, we address the important influence of abused addictive substances and polysubstance use in this review.