Making HIV Hard to Hide: An Immunotherapy Approach

Written by Alexander Egipto and Edited by Catherine Zhang

In our day-to-day life, we hardly notice any indications that our immune system is working—however, in reality, it’s constantly working to protect us from a large number of infections without impeding our everyday activities. However, some infections are malicious enough to devastate our whole immune system from the inside, such as the human immunodeficiency virus, commonly referred to as HIV. This degradation of the human immune system eventually culminates in a potentially life-threatening condition known as acquired immune deficiency syndrome, or AIDS, by which the host’s immune system is weakened to the extent in which it can no longer protect against potential infections. A particularly insidious characteristic of HIV is that it can actually enter a state of dormancy after initially affecting individuals, by which afflicted patients appear not to show any symptoms for years; however, this is when key components of our immune system are slowly dismantled by the virus as it replicates [1]. 

A key factor of this dormant period lies in HIV’s primary target: the helper T cells. These T cells are a subset of white blood cells that elicit specific responses, such as the release of antibodies from our immune system to deal with possible infections. After infection, HIV is able to insert its own genes into the DNA of helper T-cells, and effectively does nothing until the cells are activated by the presence of an infection. Once this happens, helper T cells will naturally turn their DNA into proteins, but the infected ones will also turn the viral DNA they’re housing into viral proteins—which is key to the survival of the virus [2]. These infected helper T cells essentially become viral reservoirs, where replication of the virus occurs until the cell dies and the virus is released to repeat the cycle in other host helper T cells [2].  

A great deal of research on combating HIV is devoted to finding a way around this replication mechanism. Researchers from the University of Pittsburgh have appeared to make some headway in developing a treatment that directs cells of the immune system to not only “kick” the virus out of hiding, but to also kill the infected cells hiding the virus as well [3]. The main mechanism behind this treatment involves three types of immune cells: the aforementioned helper T cells, cytotoxic T cells, and dendritic cells. Cytotoxic T cells are another subset of white blood cells that assist the immune system by killing infected cells outright [2]. Dendritic cells, on the other hand, can be thought of as the shot-caller that directs both types of T cells during the body’s immune response [4]. However, dendritic cells need some form of molecular “evidence” to present to the T cells in order to activate them; this is normally called an “antigen” and is usually taken from part of the virus. In the study, two different antigens were used, one from HIV and one from CMV, also known as cytomegalovirus. The latter is a virus that won’t typically affect individuals with working immune systems, but is capable of attacking helper T cells in immunodeficient hosts [5,6]. Researchers chose to test a CMV antigen because they suspected that T cells infected with this virus would serve as good reservoirs for HIV [3].

This brings us to the end product of this study: a dendritic cell called MDC1 that, when presenting an HIV or CMV antigen, caused infected helper T cells to reactivate and present HIV proteins [3]. In addition to this, these modified dendritic cells were then able to direct cytotoxic T cells to attack the infected helper T cells, as they were now presenting sufficient evidence of infection in the form of exposed viral proteins [3]. As these results were obtained in a laboratory setting, the researchers are hoping to move forward with further trials to test this approach in humans. There now appears to be hope for a treatment that can not only tackle the virus at a key point of infection, but also alleviate patients and their immune systems of the foreboding fate that comes with HIV. 

References:

1. Bhatti AB, Usman M, Kandi V. (2016). Current Scenario of HIV/AIDS, Treatment Options, and Major Challenges with Compliance to Antiretroviral Therapy. Cureus, 8: e515.
2. Alimonti JB, Ball TB, Fowke KR. (2003). Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J Gen Virol, 84: 1649-61.
3. Kristoff J, Palma ML, Garcia-Bates TM, Shen C, et al. (2019). Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1. EBioMedicine,
4. Klechevsky E. (2015). Functional Diversity of Human Dendritic Cells. Adv Exp Med Biol, 850: 43-54.
5. Schottstedt V, Blümel J, Burger R, Drosten C, et al. (2010). Human Cytomegalovirus (HCMV) – Revised. Transfus Med Hemother 37: 365-75.

      6. Rice GP, Schrier RD, Oldstone MB. (1984). Cytomegalovirus infects human lymphocytes and monocytes: virus expression is      restricted to immediate-early gene products. Proc Natl Acad Sci U S A 81: 6134-8.