The replication activity of HIV-1 can be influenced by various factors, including sex hormones. Recent research has highlighted the contrasting effects of female sex hormones on different HIV-1 subtypes. This article focuses on the impact of female sex hormones on the replication activity of HIV-1 sub-subtype A6 and CRF02_AG, while examining the lack of effect on HIV-1 subtype B. Understanding these subtype-specific differences can provide insights into the interplay between sex hormones and HIV-1 replication, potentially informing the development of targeted therapeutic strategies and preventive interventions. HIV-1 replication activity can be modulated by various host factors, including sex hormones. This section introduces the topic and emphasizes the contrasting effects of female sex hormones on the replication activity of different HIV-1 subtypes, specifically sub-subtype A6, CRF02_AG, and subtype B [1,2]. Understanding the subtype-specific effects of female sex hormones on HIV-1 replication can inform the development of targeted therapeutic strategies. This section discusses the potential for modulating hormone levels or targeting viral replication pathways to optimize treatment outcomes. Differences in co-receptor usage and entry pathways between HIV- 1 subtypes may contribute to the varied response to female sex hormones. This section discusses the role of co-receptor usage and entry mechanisms in the context of subtype-specific replication activity. Genetic variations within the viral genome, such as specific polymorphisms and accessory genes, may contribute to the differential effects of female sex hormones on HIV-1 subtypes. This section explores the potential genetic factors influencing the interactions between sex hormones and viral replication.