Introduction
Human Immunodeficiency Virus, or HIV, is a well-known group of viruses that has eluded sterilizing treatment for over four decades. It can be transmitted sexually (usually via unprotected intercourse resulting in contact with bodily fluids), but also vertically (from mother to child) and via blood transfusion (1). HIV infection first presents, usually in the weeks following initial infection, in an acute (immediate) phase via flu-like disease, including fever, malaise (non-specific discomfort), and rash. This is followed by a long-term asymptomatic phase, where the patient usually experiences no disease for years following infection (2). This phase is usually the result of seroconversion, wherein the patient’s CD4+ T Cells create antibodies (small molecules designed to attach to and stop the activity of the outer components of viruses) capable of eliminating the virus. However, over the course of years, the virus, which persists in low numbers, gradually eliminates the patient’s CD4+ T cells and adapts to the antibodies by changing its outer protein shape (1). This causes a gradual increase in the amount of virus the patient has, and puts them at risk for opportunistic infection (when other viruses, bacteria, fungi, or parasites take advantage of the patient's weakened defenses to infect them) (1). Once the concentration of CD4+ T cells falls below a certain concentration (200 cells per milliliter of blood), the patient is considered to have Acquired Immunodeficiency Syndrome, or AIDS (2). Death typically results from the patient being unable to fight off other infections due to the elimination of their immune cells.
Despite forty years of attempting to create a vaccine capable of reducing HIV’s burden amongst patients, no such treatment has (yet) materialized (3). Thus, the attention of the scientific enterprise has shifted toward attempting to fully understand how HIV disarms our immune cells and the ways our immune system attempts to fight back. Such studies have resulted in the creation of antivirals, small molecules that prevent the virus from replicating. Combinations of these antivirals have served as effective and life-changing treatments (1). Whereas HIV infection was once a death sentence, it has become a manageable condition.
The first line of defense our immune system has against any viral infection is its interferon (IFN) response (1). In the case of HIV-1, the interferon response is mediated by a specific class of molecules called type I interferons (IFN-Is). These molecules, upon the detection of a virus, force our cells to undergo a huge amount of internal changes, which place them into a sort of “antiviral mode”. These changes are mediated by Interferon-stimulated genes (ISGs), which change the concentration of our cells’ internal components in a way that mitigates viral spread or replication (1). The sheer number of ISGs and their effects on our cells and immune system are so numerous that science has yet to exhaustively identify them. This paper, from the State Key Laboratory of the First Hospital of China Medical University, uncovers the novel role of an ISG-induced inhibitor: ZFP36L2.
A Novel ISG-induced inhibitor: ZFP36L2 Mitigates HIV-1 Infection of Cells
Figure 1A, D: These results show that ZFP36L2 can prevent HIV-1 viruses from forming in immune cells.
The authors first tested the effect of adding ZFP36L2 to regular cells (A) or immune cells (D) to see if it had any effect on HIV-1 virus formation. They measured p24, a component of HIV-1’s outer shell, to measure the amount of virus being made. As can be seen above, adding ZFP36L2 causes a massive decrease in p24 concentration, indicating that it can potentially stop HIV-1 replication in T Cells. HIV-1 typically causes death because its long-term replication in CD4+ T cells leads to their elimination. This leaves the patient extremely vulnerable to parasites, fungi, bacteria, and other viruses that are normally dealt with by these cells. Thus, if ZFP36L2 can stop HIV-1 from replicating in T Cells, it may be possible to use it to prevent these opportunistic infections and other damage caused by the virus. In subsequent tests, the authors found that ZFP36L2 specifically targets “primate lentiviruses” (a class of viruses that infect humans and primates, of which HIV-1 is one member), which means that it may be possible to use it to fight HIV-1 without triggering the entire immune system (which can also be dangerous). Finally, the authors find through yet more experiments that ZFP36L2 is indeed an interferon-stimulated gene-induced inhibitor, becoming activated by the presence of IFNβ.
ZFP36L2: How does it work?
After the authors established that ZFP36LR is an ISG-induced inhibitor capable of reducing HIV replication in immune cells, they sought to understand more fully, and to the molecular level, how the protein worked. At this scale (the scale of proteins), activity is mainly determined by shape. You can think of proteins as highly complex puzzle pieces capable of interacting with other proteins, which can change what they can do. Thus, the authors ran further experiments to figure out which proteins ZFP36L2 interacted with, as doing so could provide insights on how to use designed molecules to activate ZFP36L2, and thereby fight HIV infections. In their first set of experiments, the authors find that when ZFP36L2 is given to cells, there are remarkable changes to the movement of genetic materials (Fig. 2G). When HIV-1 is ready to build new viruses, it needs to deliver its genetic code from the nucleus, where they’re created, to the cytoplasm, where they are translated into proteins that form the viruses. However, when ZFP36L2 is present, this material remains in the nucleus, except for fully spliced transcripts. In general, before human cells can “translate” genetic material into proteins, they must first be cut and fashioned into specific configurations. These fully configured materials pass through unaffected, but partially configured materials (including HIV-1’s genetic code) remain stuck in the nucleus. Thus, it seems that ZFP36LR prevents HIV-1 from passing down its genetic information, which is needed to make successful viruses. Notably, all the arrested materials contain a Rev Response Element, or RRE. This is, essentially, a genetic “pattern” that the HIV-made protein Rev can interact with (that is, it has a specific shape). These points lead the authors toward exploring Rev’s interactions with ZFP36L2.
Fig 3B,D: These graphs show the level of genetic material being made without and with ZFP36L2, without (B) and with (D) the aforementioned RRE.
The above results show that, when RRE’s are present (such as on the HIV’s genetic code) and ZFP36L2 is present, the amount of genetic material being created massively decreases. This indicates that ZFP36LR uses Rev to interact with RREs and prevents them from leaving the nucleus, thereby preventing HIV-1 from acquiring copies of its genetic code. Later experiments confirmed that ZFP36LR directly interacts with Rev.
ZFP36LR: Can it Really Treat Patients in the Real World?
Having found whether and how ZFP36LR can mitigate HIV-1 infection of immune cells is astonishing. However, these experiments, like many, were performed using highly modified cells in conditions wholly alien to those inside a patient. Thus, while a relationship between ZFP36LR and HIV infection can be established, it is still difficult to definitively say whether activation of ZFP36LR could be used as a future antiviral against HIV-1 in patients. At the same time, doing such experiments on living humans comes with major ethical and moral concerns, as these are highly experimental and thereby risky techniques. Thus, the authors decided to use an ex vivo model. When scientists perform experiments like these, they tend to use immortalized cells (cells that have been modified or otherwise mutated to replicate indefinitely) in highly artificial environments. These are known as in vitro experiments. Performing experiments on a patient would be in vivo. Ex vivo, then, occupies a sort of middle ground. In this case, the authors extracted CD4+ T cells from HIV patients and performed experiments on them in an artificial environment. These cells will be nearly identical to those in patients, so the results from such experiments will be more applicable in clinical settings. At the same time, these experiments come at no risk to any would-be test subjects. Thus, with an ex vivo model, the authors tested to see the effect of adding IFNβ to HIV-1 replication and ZFP36LR concentrations.
Fig. 6I, J: These graphs show the concentrations of virus (I) and genetic material encoding ZFP36LR (J) with and without IFNβ.
As can be seen above, when IFNβ is added to the patients’ cells, the amount of virus massively decreases, while the concentration of genetic material creating ZFP36LR massively increases. When ZFP36LR creation is blocked, this decrease in HIV-1 concentration disappears, indicating that activating IFNβ in patient cells is capable of activating ZFP36LR and mitigating HIV-1 replication.
Conclusion
The set of experiments the authors conducted demonstrates that ZFP36LR is a protein created by an ISG, which is activated by IFNβ, and interacts with HIV-1’s genetic code to prevent it from replicating. More excitingly, the ex vivo experiments indicate that IFNβ activation can successfully mitigate HIV-1 infection of immune cells within patients through this mechanism, which has massive implications for antiviral design. IFNβ is unfortunately a pleiotropic protein (a protein with many roles and functions), so it’s not feasible to simply activate it in HIV-1 patients. Doing so would have any number of side effects, given its central role in the wider antiviral responses of our cells. ZFP36LR, by contrast, seems to be specific to targeting HIV-1, so future antivirals could come in the form of IFNβ analogues (molecules that mimic the shape of IFNβ, but that only activate ZFP36LR). As the battle against HIV-1 wages on, studies like these uncover ever more targets against HIV-1, expanding the options for treatment for HIV-1-infected patients. Although a sterilizing treatment for HIV-1 continues to elude science, discoveries such as these continue to improve the outcomes of millions living with HIV.
References
Gilroy, S.A., (2025, January 3). HIV Infection and AIDS Clinical Manifestation. Medscape,
https://emedicine.medscape.com/article/211316-clinical.
(No Authors), (2025, January 14). About HIV. Center for Disease Control,
https://www.cdc.gov/hiv/about/index.html.
Shim, I., Rogowski, L., & Venketaraman, V. (2025). Progress and Recent Developments in HIV
Vaccine Research. Vaccines, 13(7), 690. https://doi.org/10.3390/vaccines13070690.
Pang, H., Cui, H., Yin, X. et al., (2026). ZFP36L2 is an interferon β -induced inhibitor that
restricts the nuclear export of HIV-1 transcripts. Nature Communications, https://doi.org/10.1038/s41467-026-71474-0.
