Dendritic cells: The key in the battle against HIV

By: Silvia Tosolini

As finding a cure for HIV feels like a maze of locked doors, dendritic cells (DCs) emerge as the master key, unlocking the path to finding new treatment possibilities. HIV (human immunodeficiency virus) is a virus that infects the body’s immune system. Presently, there is no effective cure: once people have it, they have it for life. Since its outbreak, HIV has infected more than 75 million people and is responsible for the death of more than 39 million¹. Moreover, people living with HIV face many issues, such as criminalisation and sexual stigmatisation, making it even more important to find a cure. What makes an HIV infection incredibly difficult to treat is the virus’s predisposition towards immune cells (T cells), as well as its capacity of hiding within those cells. This way, it remains in a dormant state and undetected for long periods of time, establishing a so-called “latent reservoir”. Considering the crucial role of T cells in fighting infections, such targeting causes a weakening of the patient’s immune system, leading to a condition called acquired immunodeficiency syndrome (AIDS). In people with AIDS, regular immune functions are not working properly, leading to an increased susceptibility for common infections, with some developing cancer^4,5. Current therapeutic options mostly consist of antiretroviral therapies (ART), which act by stopping the virus from producing more copies of itself, so that the patient’s immune system is restored and they can live a longer and healthier life⁴. Even so, ART cannot be considered a cure as it is not effective in eradicating HIV completely, due to the virus’s ability to establish the latent reservoir and hide. Therefore, more options are being explored⁵. Recently, significant attention has been directed toward DCs and their ability to shape immune responses. New research brought forth captivating insights and promising prospects for potential breakthroughs in HIV treatment.

The immune system and the role of DCs

Our immune system is a complex network of organs, cells, proteins, and chemicals, constantly working together to protect us against a large variety of pathogens and foreign substances. Interestingly, it is composed of two systems that involve different players and tasks but are closely associated. The innate immune system consists of a first-line defense against unknown organisms and substances entering the body, whereas the adaptive immune system offers a more specific and powerful response. DCs link these two responses by acting as “guards”, ready to capture and process foreign pathogens and activate immune cells, such as T cells, thereby inducing a specific adaptive immune response¹. What is interesting about DCs is that they play a dual role when it comes to HIV. On one hand, they can inadvertently assist the spread of HIV, while on the other hand, they hold the potential to activate the immune system to fight against it.

DCs as mediators of HIV-spreading and reservoir formation

Considering the central role of DCs in the activation of specific immune responses, their involvement in mediating HIV spreading has been widely researched. Given the virus’s preference for T cells, it has been hypothesised that DCs could act as a “transfer tool” and facilitate HIV transmission to the lymph nodes, where most of these target cells reside. The virus is mainly spread through sexual contact, as it enters the body via the skin surface of the genital areas. At these sites, DCs are extremely prominent and are the first to interact with HIV. There are two ways that DCs can transmit HIV to T cells: cis-infection and trans-infection. In cis-infection, the virus infects the T cell and produces new viral particles that are released into the environment. In trans-infection, the DCs act as a mediator and can transmit the virus to T cells through a specific interaction called a “virological synapse”, or by using exosomes to carry the virus to the T cell² (Figure 1).

Among the many subtypes of DCs under study, only certain ones stand out as key contributors to the virus’s spread and the formation of a hidden reservoir. Dermal immature DCs, which reside in the skin, are among the first cells to come in contact with the virus, and exhibit remarkable ability to transmit it to T cells within lymph nodes³. Blood-resident plasmacytoid DCs can regulate T cell-recruitment and immune activation to favour HIV pathogenesis. Finally, follicular DCs, located within the B cell follicle in direct contact with T cells, have also been found essential for sustaining the establishment and long-term persistence of the viral infection^4,5,6.

The therapeutic potential of DCs in the battle against HIV

As previously mentioned, HIV’s ability to establish a latent reservoir and remain hidden represents a major door, which has been incredibly difficult to unlock^6,7. Thus, current research is focusing on the development of new therapeutic tools. One approach, the “shock and kill” strategy, is based on forcing the virus out of its hiding, thereby making it visible and vulnerable to the immune system, which will eventually eliminate it⁸. However, this approach does not lead to complete HIV elimination due to the weak immune response that follows viral reactivation and the low reactivation rates⁹. Therefore, because of their clear involvement in HIV pathogenesis, scientists are now exploring the potential of harnessing DCs for the development of a more effective therapy to eliminate the viral reservoir.

DCs have been found to be central in presenting HIV-specific antigens to T cells, inducing powerful responses capable of controlling viral replication¹⁰. Moreover, it was found that DCs can function as potential “latency-reversing agents” by reactivating the virus^11,12, as shown in Figure 2. Among different subsets of DCs, primary myeloid DCs isolated from the bloodstream have emerged as potent keys in unlocking these major doors and clearing the path towards new possibilities.

More studies and clinical trials have to be performed to gain a better idea of the possible side effects associated with these approaches and to evaluate their efficacy in eradicating the virus. However, these results show that DCs hold great potential in reactivating the virus and in inducing long-term strong immune responses. As we continue to explore the possibilities, DCs emerge as the master key, unlocking the way to innovative therapeutic strategies. By utilising them, we open the doors to potential treatments that not only manage the virus but hold the promise of defeating it.

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Further reading:

1. Fucikova, J., Palova-Jelinkova, L., Bartunkova, J., & Spisek, R. (2019). Induction of tolerance and immunity by dendritic cells: mechanisms and clinical applications. Frontiers in immunology, 10, 2393. https://doi.org/10.3389/fimmu.2019.02393. ↩︎
2. Coleman, C. M., Gelais, C. S., & Wu, L. (2013). Cellular and viral mechanisms of HIV-1 transmission mediated by dendritic cells. HIV Interactions with Dendritic Cells: Infection and Immunity, 109-130. https://doi.org/10.1007/978-1-4614- -6_4. ↩︎
3. Rhodes, J. W., Tong, O., Harman, A. N., & Turville, S. G. (2019). Human dendritic cell subsets, ontogeny, and impact on HIV infection. Frontiers in immunology, 10, 1088.  https://doi.org/10.3389/fimmu.2019.01088. ↩︎
4. Cohn, L. B., & Deeks, S. G. (2020). The immune response fails to control HIV early in initial virus spread. The Journal of clinical investigation, 130(6), 2803-2805. https://doi.org/10.1172/JCI136886. ↩︎
5. Mitchell, J. L., Takata, H., Muir, R., Colby, D. J., Kroon, E., Crowell, T. A., … & Trautmann, L. (2020). Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption. The Journal of clinical investigation, 130(6), 2845-2858. https://doi.org/10.1172/JCI130597. ↩︎
6. Aquaro, S., Borrajo, A., Pellegrino, M., & Svicher, V. (2020). Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages. Virulence, 11(1), 400-413. https://doi.org/10.1080/21505594.2020.1760443. ↩︎
7. Busman-Sahay, K., Starke, C. E., Nekorchuk, M. D., & Estes, J. D. (2021). Eliminating HIV reservoirs for a cure: the issue is in the tissue. Current Opinion in HIV and AIDS, 16(4), 200. DOI: 10.1097/COH.0000000000000688. ↩︎
8. Lichterfeld, M. (2020). Reactivation of latent HIV moves shock-and-kill treatments forward. Nature, 578, 42-43. https://doi.org/10.1038/d41586-020-00010-x ↩︎
9. Kristoff, J., Rinaldo, C. R., & Mailliard, R. B. (2019). Role of dendritic cells in exposing latent HIV-1 for the kill. Viruses, 12(1), 37. https://doi.org/10.3390/v12010037. ↩︎
10. Sengupta, S., & Siliciano, R. F. (2018). Targeting the latent reservoir for HIV-1. Immunity, 48(5), 872-895. https://doi.org/10.1016/j.immuni.2018.04.030. ↩︎
11. van Montfort, T., van der Sluis, R., Darcis, G., Beaty, D., Groen, K., Pasternak, A. O., … & Berkhout, B. (2019). Dendritic cells potently purge latent HIV-1 beyond TCR-stimulation, activating the PI3K-Akt-mTOR pathway. EBioMedicine, 42, 97-108. https://doi.org/10.1016/j.ebiom.2019.02.014. ↩︎