By: Sabrina Ahmed, PharmD Candidate c/o 2017

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Over the decades, one of the biggest mysteries encountered by researchers has been why so many CD4 T-cells die when one is infected with Human Immunodeficiency Virus (HIV).¹ CD4 T-cells are an integral part of the immune system as they locate pathogens and signal other immune cells for the destruction of the pathogen. The HIV attacks these cells, and as the number of CD4 T-cells are depleted, the patient becomes more susceptible to “opportunistic infections,” or infections that he or she would normally be able to fight off. Typically, a healthy individual has a CD4 T-cell count of between 500-1500 cells/mm³. HIV treatment begins when a patient’s CD4 T-cell count drops below 350 cells/mm³ and an individual is considered to have AIDS when this count becomes 200 cells/mm³ or fewer.² While treatment with anti-retroviral drugs (ARVs) has helped HIV patients live longer by keeping the disease in a period of latency, a new drug has shown promise in aiding patients when the HIV virus starts killing off these T-cells rapidly.³

Why CD4 T-cells die so rapidly in HIV infections has never been properly understood, but researchers have speculated that a specific type of apoptosis is involved.¹ Scientists have known that some T-cells become virus-replicating units while the rest of the T-cells become resting cells, which are infected by HIV that do not replicate the virus. Researchers proposed that the infected T-cells either died from having too much of the virus in them, causing the T-cells to burst, or from the immune system’s innate suicide signals that prevent further spread of the virus. The former occurs in replicating cells, and the latter occurs in resting CD4 T-cells. Scientists believed the majority of CD4 T-cell deaths results from those that actively replicate the virus. However, the number of infected cells is too low to account for the high death toll of CD4 T-cells in HIV patients.⁴ They were aware that a small fraction of T-cells underwent a “capsase-3-mediated” apoptosis, but this process only accounted for about 5% of the total CD4 T-cell deaths, which includes both resting and replicating cells.¹ Researchers at Greene laboratory at Gladstone Institute of Immunology and Virology have revealed that the other 95% of T-cell death, including that of the resting cells, is caused by a process called pyroptosis.^1,5 This process is mediated by capsase-1, an enzyme that initiates inflammatory responses, which is triggered by an abortive viral infection, when the infected cell is not able to replicate the virus. In pyroptosis, a type of programmed cell death that results in a severe inflammatory response, pro-inflammatory cytokines are released, attracting more CD4 T-cells to the site and prompting these cells to undergo pyroptosis as well. This causes a large number of CD4 T-cells to die. The discovery of the mechanism of pyroptosis has helped explain the two hallmark signs of AIDS, which are CD4 T-cell depletion and chronic inflammation.¹

While most studies that dealt with infected CD4 T-cells haven’t been able to explain the death of resting CD4 T-cells, the discovery of pyroptosis in HIV progression has shed light on the this matter. The scientists at Gladstone started looking for ways to halt pyroptosis by studying the spleen, tonsil, and lymph-node tissue samples from HIV-infected patients. This revealed that in the cells that experience abortive infection, there are fragments of HIV DNA left behind, which trigger pyroptosis. Researchers manipulated genetic information in the CD4 T-cells in spleen and tonsil tissues to determine what part of the cell recognizes the HIV DNA fragments and prompt caspase-1 to initiate cell suicide and the accompanying inflammation.⁵ Analyzing the DNA of the T-cells using mass spectroscopy and using the process of elimination yielded a protein called IFI16 to be the target for this process.⁴ In the presence of HIV DNA fragments, IFI16 sends signals to caspase-1, which activates pyroptosis.⁵

The discovery of the exact mechanism by which resting CD4 T-cells undergo pyroptosis may be integral in slowing down the progression of HIV. Once the body detects the deaths of these CD4 T-cells, it produces more T-cells. Unfortunately, the body cannot keep up with the rate of loss of the cells, which leads to the onset of AIDS, and rendering the patient vulnerable to opportunistic infections. To our advantage, a new anti-inflammatory drug under clinical trials targets pyroptosis. Vx-765, under development by Vertex Pharmaceuticals, may be able to block the enzyme caspase-1 and halt T-cell death.^3,6 Phase 2 trials have been proposed in which the drug and ones similar to it will be tested for its ability to block inflammation and pyroptosis in infected hosts. While it will take many years before this drug may be considered an option of HIV therapy, being able to find agents that target the pathway shows promise.

HIV virus quickly develops drug resistance to traditional ARVs; however, anti-inflammatory drugs like VX- 765 would target the host’s pathway instead of the virus, bypassing the mechanism of resistance. Furthermore, the anti-inflammatory drug could act as a bridge therapy for those who do not have access to ARVs.  Targeting pyroptosis could also delay the onset of age-related diseases such as dementia, heart attacks, and cancer that are exacerbated by inflammation.⁶ Reduced inflammation would also slow down the expansion of the latent virus in the body, leading to slower progression of HIV to AIDS.⁵ Drugs such as VX-765 may stop the “body’s own destructive response to HIV,” according to Dr. Kathryn Monroe, one of the two leading authors of the study at Gladstone lab.⁶

 

SOURCES:

1. Gilad Doitsh, Nicole L. K. Galloway, Xin Geng et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 2014;505,509-514. Accessed April 6, 2014.
2. CD4 Count (or T-cell Count). U.S. Department of Veteran Affairs Website. http://www.hiv.va.gov/patient/diagnosis/labs-CD4-count.asp. Updated October 17, 2013. Accessed May 15, 2014.
3. What is HIV/AIDS? – HIV Basics – HIV/AIDS. Center for Disease Control and Prevention Website. http://www.cdc.gov/hiv/basics/whatishiv.html. Updated February 12, 2014. Accessed April 12, 2014.
4. Kim M. New Studies Detail How HIV Affects Immune System, Claim Drug Exists to Block Virus. Washington Post. http://www.washingtonpost.com/national/health-science/new-studies-detail-how-hiv-affects-immune-system-claim-drug-exists-to-block-virus/2013/12/19/1697afea-68c9-11e3-a0b9-249bbb34602c_story.html. Accessed April 12, 2014.
5. Scientists Discover How Key Immune Cells Die During HIV Infection and Identify Potential Drug to Block AIDS: Gladstone Plans to Launch Phase 2 Trial with Existing Anti-Inflammatory. University of California, San Francisco. http://www.ucsf.edu/news/2013/12/110841/scientists-discover-how-key-immune-cells-die-during-hiv-infection-and-identify. Accessed April 12, 2014.
6. Julie Steenhuysen. Twin U.S. Studies Unlock Mystery of How HIV Causes AIDS. Reuters Website. http://www.reuters.com/article/2013/12/19/us-aids-science-idUSBRE9BI14H20131219. Accessed May 15, 2014.

[pubmed_related keyword1=”HIV” keyword2=”AIDS” keyword3=”progression”]