TNF-α exists as a homotrimer and has two active forms: membrane-bound (mTNF-α) and soluble (sTNF-α), which differ significantly in synthesis, release, and function. mTNF-α is the initial precursor form of TNF-α, anchored to the cell membrane via a transmembrane domain, and is primarily expressed on activated immune cells such as macrophages, T cells, and natural killer cells. It mediates local, cell‑contact‑dependent signaling, acting mainly on adjacent target cells, and can also conduct reverse signaling to regulate the function of the cell on which it is expressed. sTNF-α is released from mTNF-α by proteolytic cleavage via metalloproteinases into the bloodstream, exerts distant endocrine effects, and is the major mediator of systemic inflammatory responses.

In terms of functional division, mTNF-α preferentially activates TNFR2 and is involved in immune regulation, tissue repair, and lymphocyte homeostasis. In contrast, sTNF-α primarily binds to TNFR1, driving strong pro‑inflammatory responses and apoptosis. Due to its short half‑life and high diffusion capacity, elevated sTNF-α levels are closely associated with systemic inflammatory diseases such as sepsis and rheumatoid arthritis; mTNF-α is more involved in local immune synapse formation and maintenance of the chronic inflammatory microenvironment.

Although TNFR1 and TNFR2 both belong to the TNFR superfamily, they differ markedly in structure, expression distribution, and downstream signaling pathways. TNFR1 is widely expressed on almost all nucleated cells and contains a death domain (DD) in its intracellular region, enabling it to recruit adaptor proteins such as TRADD, FADD, and RIPK1, thereby initiating three major signaling pathways: the NF-κB pathway, the apoptotic pathway, and the necroptotic pathway. Thus, TNFR1 acts as a “double‑edged sword”: under normal physiological conditions, it maintains cell survival and inflammatory defense; upon excessive activation or when caspase‑8 is inhibited, it induces cell death.

In contrast, TNFR2 is primarily expressed on immune cells and endothelial cells. Its intracellular region lacks a death domain and instead activates the NF-κB and PI3K/Akt pathways through proteins such as TRAF2 and cIAP1/2, mainly promoting cell proliferation, survival, tissue repair, and immune regulation. TNFR2 signaling enhances the suppressive function of regulatory T cells and promotes memory formation in CD8+ T cells. Notably, TNFR2 can competitively bind TNF-α, with a particularly higher affinity for mTNF-α, thereby limiting TNFR1‑mediated pro‑apoptotic signaling. This cross‑regulation between the two receptors forms a complex signaling network: in HIV‑1 infection, viral proteins often disrupt immune homeostasis by upregulating TNFR2 expression, contributing to immune exhaustion.

Multiple HIV-1-encoded proteins hijack the TNF/TNFR signaling axis through direct or indirect mechanisms, aberrantly activating the downstream transcription factor NF-κB and thereby promoting viral gene transcription. Specific mechanisms include: the Vpr protein interacts with host TRADD, GR, and p65 (RelA), enhancing TNFR1-mediated NF-κB nuclear translocation while inhibiting the anti-inflammatory effects mediated by the glucocorticoid receptor. The Tat protein, a potent transcriptional activator, not only binds Cyclin T1 to promote RNA polymerase II elongation but also directly activates the IKK complex, leading to IκBα phosphorylation and degradation, resulting in sustained NF-κB nuclear entry.

Additionally, gp120 binds to the host CD4 receptor and co-receptors CCR5/CXCR4, activating downstream PI3K/Akt and MAPK pathways and indirectly upregulating surface expression levels of TNFR1 and TNFR2, making cells highly sensitive to TNF-α signaling and further amplifying NF-κB-driven HIV-1 long terminal repeat (LTR) transcriptional activity. The Nef protein downregulates MHC-I and CD4 to evade host immunity while activating PAK2 kinase to promote NF-κB nuclear entry. The synergistic action of these viral proteins significantly enhances HIV-1 replication efficiency in a chronic inflammatory microenvironment while inducing T cell apoptosis and immune exhaustion, forming a vicious cycle of “inflammation – viral replication – immune damage.”

Under physiological conditions, the TNF/TNFR signaling axis is a key regulatory hub for innate and adaptive immunity. On one hand, upon pathogen invasion, locally released TNF-α activates macrophages and dendritic cells, promotes the secretion of pro-inflammatory mediators such as IL-1, IL-6, and chemokines, and enhances phagocytosis and antigen presentation, thereby rapidly clearing pathogens. At the same time, TNF-α promotes the expansion and functional maintenance of regulatory T cells (Tregs) through TNFR2 signaling, preventing excessive inflammatory tissue damage – this represents its “immune regulatory” side.

On the other hand, TNF-α also participates in the fine regulation of adaptive immunity by promoting T cell differentiation toward Th1, B cell antibody class switching, and germinal center formation, thereby enhancing immune memory. However, when HIV-1 proteins persistently and aberrantly activate this pathway, the pro-inflammatory effects of TNF-α become dominant, leading to a chronic inflammatory state characterized by persistently elevated levels of IL-6, CRP, and TNF-α itself in the blood. This chronic inflammation not only causes excessive activation of CD4+ T cells and renders them susceptible to activation-induced cell death (AICD) but also induces high expression of immune checkpoint molecules, driving T cell exhaustion. Meanwhile, TNF-α-mediated fibrosis and destruction of lymphoid tissue further impair immune reconstitution. Thus, once the balance between “defense” and “damage” in the TNF/TNFR axis is disrupted by HIV-1, it becomes a key driver that mutually exacerbates immune deficiency and inflammatory dysregulation.