Acquired Immune Deficiency Syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). The viral architecture comprises two primary protein categories: surface glycoproteins that form the viral envelope and internal structural components. These internal proteins include the major capsid protein p24, matrix protein p17, and nucleocapsid protein p12, along with essential enzymatic elements including RNA-dependent DNA polymerase (reverse transcriptase), proteolytic enzyme (protease), and viral integration enzyme (integrase). HIV infection directly compromises the immune system, rendering the host susceptible to various opportunistic infections and increasing the risk of malignancie (Dusingize et al., 2024). Despite advances in research, no effective vaccine or definitive cure for AIDS has been developed. The persistent rise in HIV infection rates underscores the urgent need for innovative strategies to combat HIV.

Currently, most patients with AIDS undergo highly active antiretroviral therapy (HAART), which slows viral replication but does not eradicate the virus (Ward et al., 2021). Furthermore, HAART faces challenges such as drug resistance, long-term toxicity, and poor reservoir penetration (Lipshultz et al., 2012). Recent research efforts have focused on vaccine development, but clinical outcomes have been unsatisfactory, and no candidate has achieved widespread clinical application (Excler and Michael, 2016). Consequently, the search for safe, effective, and low-cost therapeutic strategies to inhibit HIV-1 remains an ongoing challenge.

The rhizomatous herb Curcuma longa, belonging to the Zingiberaceae (ginger) family, has been used in traditional medicine since its inclusion in Xinxiu Materia Medica (Newly Revised Materia Medica). It possesses significant medicinal value, including hepatoprotective, antihypertensive, and antispasmodic properties. Curcumin, a bioactive compound extracted from turmeric rhizomes, has demonstrated anti-inflammatory and antitumor properties and has been implicated in the treatment of various diseases (Kocaadam and Şanlier, 2017). Notably, curcumin has been identified as an inhibitor of HIV integrase (Mazumder et al., 1995)and protease (Prasad and Tyagi, 2015), effectively suppressing HIV replication.

Forkhead box protein P3 (FOXP3) is a transcription factor critical for regulatory T cells (Tregs) and plays an essential role in regulating Treg function (Dong et al., 2021). In HIV infection, Tregs can inhibit antiviral immunity, allowing viral persistence, but also curb harmful inflammation (Kleinman et al., 2018). Moreover, HIV-1 infection upregulates FOXP3 in Tregs, creating a feedback loop that favors immune evasion (Holmes et al., 2008). However, FOXP3-Tregs may serve as reservoirs for latent HIV due to their survival advantage.

The C-C chemokine receptor type 5 (CCR5) plays an essential role as a co-receptor in mediating human immunodeficiency virus (HIV) cellular entry. This G protein-coupled receptor enables viral attachment and subsequent membrane fusion, serving as a crucial component in the initial stages of HIV infection. After invading the host, HIV binds to CD4 molecules while requiring CCR5 for successful infection. The viral envelope glycoprotein 120 (gp120) initially binds to CD4 and undergoes conformational changes, exposing the gp41 binding site and promoting fusion of the viral envelope with the host cell membrane (Colin et al., 2013). Studies utilizing CRISPR-based gene editing to knock down CCR5 expression in humanized mouse models have effectively eliminated HIV (Dash et al., 2023). In immunomodulation, CCR5 mediates chemotaxis of immune cells (such as T cells, macrophages) to inflammation sites. Paradoxically, its overexpression in chronic HIV infection may enhance viral spread while contributing to immune hyperactivation. This highlights CCR5 as a pivotal therapeutic target in combating HIV infection. By concurrently suppressing CCR5-mediated viral entry and FOXP3-driven immune evasion, curcumin addresses two pillars of HIV-1 pathogenesis. This dual action contrasts with single-target HAART drugs, offering a strategy to mitigate resistance and latency.

The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway serves as a fundamental regulatory mechanism involved in multiple physiological functions and has been associated with various pathological conditions. This evolutionarily conserved signaling network contributes to essential cellular processes while its dysregulation is frequently observed in human diseases. Activation of this pathway has been associated with tumorigenesis (He et al., 2021)and inflammation (Acosta-Martinez and Cabail, 2022). Previous studies have demonstrated that inhibiting the PI3K/AKT pathway can eliminate HIV-1-infected cytoprotective macrophages, providing a potential therapeutic strategy for HIV-1 treatment (Jeong et al., 2014).

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) cascade, which is controlled by multiple cytokine signals, represents a crucial regulatory system for immune function modulation. Like other key signaling networks, this pathway mediates essential cellular communication events that govern immunological homeostasis (Gotthardt et al., 2019, Huang et al., 2022). Inhibition of the JAK/STAT pathway has been shown to downregulate CCR5 expression (Wang et al., 2024), while activation of this pathway by interferons effectively inhibits HIV replication (Liu et al., 2012).

Given the dual roles of CCR5 in viral entry and FOXP3 in immune suppression, we hypothesized that curcumin inhibits HIV-1 by disrupting CCR5-mediated entry and FOXP3-driven immune evasion via PI3K/AKT and JAK/STAT pathways. This crosstalk, hitherto unexplored in the context of natural compounds, could simultaneously block viral replication and restore immune surveillance.