The HIV regulatory protein Tat (Trans-activator of Transcription) plays a central role in HIV infection, including HIV acquisition, regulation of virus gene expression/replication, and disease progression. The expression of Tat and its cellular cofactors are essential for productive virus replication. Restrictions of Tat expression lead to the establishment of latency, thus governing HIV reservoir dynamics. In infected cells, Tat also induces the expression of chemokines that can recruit activated T cells and monocyte/macrophages to the sites of infection, thus promoting HIV dissemination. Additionally, Tat downregulates major histocompatibility complex class I and II surface molecules, damping cell-mediated adaptive immunity against HIV.

In addition to its intracellular activities, extracellular Tat (eTat) can promote cell-cell interactions. At the peak of acute infection, high levels of Tat are released from infected cells and bind the extracellular matrix via heparan sulfate proteoglycans. This creates long-lasting chemotactic gradients that, due to molecular mimicry, recruit HIV target cells, fuelling further rounds of infection. eTat also binds Env, which enhances viral spread through various mechanisms. First, Tat binding to Env favors HIV-1 capture by dendritic cells, a key event for virus acquisition at the mucosal portal of entry. The Tat/Env interaction redirects HIV from C-type lectin receptors to the RDG-binding integrins, making ineffective anti-HIV antibodies. At the same time, eTat stabilizes the open conformations of Env, increasing HIV infectivity for CD4+ T cells. Consequently, containment of infection at the portal of entry was observed in macaques vaccinated with Tat and Env and challenged intrarectally with SHIV.

Finally, Tat also contributes to the residual inflammation/immune dysregulation in virologically suppressed people with HIV-1 (PWH), which occurs despite antiretroviral therapy (ART), because ART does not prevent latent HIV reactivation and gene expression. Tat alters the functionality of multiple physiological systems, including the immune, cardiovascular, and nervous systems. contributing to the development of a plethora of co-morbidities, including Kaposi’s sarcoma and other tumors, hypertension, coronary artery disease, diabetes, osteoporosis, and neurological disorders.

As Tat impacts immune dysregulation, both humoral and cellular anti-Tat immunity appear to be protective. Anti-Tat antibodies, only infrequently found in PWH, are associated with delayed progression to disease and a faster and better response to ART. Similarly, vaccine studies in macaques have shown prevention/containment of infection by pathogenic SHIVs, while cART-treated, virologically suppressed PWH vaccinated with Tat experienced a substantial immune restoration and accelerated proviral load decay as compared to control.

This special issue will present the first comprehensive overview by the leading researchers in the field of Tat's diverse molecular, immune, and physiological functions. In addition to addressing Tat's many roles in HIV-1 infection and disease pathogenesis, the issue will also highlight the protective role of anti-Tat immunity.

The new insights into Tat presented in the issue will be instrumental for the development of preventative and therapeutic intervention strategies targeting Tat toward HIV prevention and cure.

Brief Research Reports, Case Reports, Clinical Trials, Original Research, Perspective, and Review articles are welcome.

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Frontiers in Immunology

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