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Even though there is no cure for HIV yet, studying how proteins interact with genes may highlight compounds that will keep it dormant.
Human immunodeficiency virus (HIV) is a virus that attacks immune cells that help the body fight infection, making a person more vulnerable to other infections and diseases. It is spread by contact with certain bodily fluids of an individual with HIV. If untreated, HIV can lead to acquired immunodeficiency syndrome (AIDS; Palmisano and Vella 2011). When HIV infects cells, it can either become active and make the individual sick or remain latent. Latency is a phenomenon where the virus exploits the cell it resides in and either begins making more copies of itself or remains dormant (Lu et al. 2021). A particular challenge with HIV is keeping these viral reservoirs latent.
The human body cannot get rid of HIV and no effective HIV cure exists. However, by taking antiretroviral therapy, people with HIV can live long and healthy lives and prevent transmitting HIV to others. Antiretroviral therapy prevents HIV from making copies of itself, which reduces the amount of HIV in the body. Having less HIV in the body gives the immune system a chance to recover and produce more protection through immune cells. Even though there are still some viral reservoirs in the body, the immune system is usually strong enough to fight off future infections (Palmisano and Vella 2011). Other nonretroviral HIV drug treatments attempt to block healthy cells from becoming infected by the virus. However, because there is no way to know when the latent viral reservoirs will become active and produce more copies of itself, HIV-positive patients have to remain on antiretroviral therapy all their lives to prevent the HIV virus from rebounding (Lu et al. 2021).
There are two types of HIV drug treatment strategies: “shock and kill”, where cells taken over by HIV are activated, targeted, and killed, and “block and lock”, where the drug prevents other body cells from being infected and forces the virus into a deep latent state (Lu et al. 2021). There are limitations to both approaches. For “shock and kill”, there are always some leftover HIV reservoirs that do not get activated and then killed by immune cells. For “block and lock”, there are not many drugs that have been discovered that effectively keep HIV latent. Therefore, Lu et al. (2021) set out to address this missing information by creating a new way to look for compounds that keep HIV dormant.
Gene expression in living cells is a complex process of various likely chemical reactions, leading to products such as messenger RNA and proteins (Jia et al. 2017). The reactions that help the cell perform a variety of roles are usually instigated by spontaneous variations in gene expression caused by a variety of factors. Considering the complexity of genetic regulatory networks, analyzing this noisy data for corresponding compounds that cause the fluctuations may seem like a daunting task. However, recent advances in proteomics techniques have resulted in the generation of large amounts of single-cell gene expression data that take into account all the possible fluctuations by a single compound in question.
Because the transition from latency occurs randomly, Lu et al. (2021) decided to measure the fluctuations in gene expression from immune cells infected with HIV in the presence of different compounds that promote viral latency. The resulting data would provide more coverage than data measuring average gene expression, leading to new drugs to consider as therapeutic agents that would normally be overlooked.
The authors began by imaging cells in the presence of 1,806 different compounds in 15-minute intervals for 48 hours. Then they looked at maps of the variance (or noise) to identify which drugs can modulate, or alter, gene expression. 279 compounds were found to modulate gene expression and the top 115 drugs were selected to gauge their potential at promoting latency in immune cells infected with HIV. Exposing all 115 drugs to cells containing dormant HIV, they measured HIV-positive cells 24 hours later and discovered only three compounds promote viral latency. Of the three compounds, two of the compounds are related to inhibition of reduction-oxidation gene regulation, which allows genes to be more or less expressed depending on how much oxygen is present and regulate which proteins the cell needs depending on their environment (Trachootham et al. 2008). Considering the impact this inhibition may have on HIV expression, the authors added compounds to the analysis that are known to inhibit reduction-oxidation regulation, leading to the discovery of two more compounds that promote latency.
Altogether, Lu et al. (2021) found a total of five HIV-suppressing compounds. Importantly, one of these compounds is already FDA-approved and commercially available. With new high-throughput technologies like the one utilized in this study, research for new compounds for treatment of HIV may accelerate, but may also be applied to other complex diseases like cancer. Additionally, drugs that would have been overlooked because their relations are only clear with certain environmental conditions may now be included in analysis, allowing the potential to repurpose drugs. Ultimately, the findings of this study and its expansion of known “block and lock” compounds may lead to an eventual effective, safe, and functional cure for HIV-infected individuals.
Rachel Hendricks is a senior at Davidson College expected to graduate with a Bachelor’s degree in Biology in May 2021. Contact her at rahendricks@davidson.edu
Resources
Jia C., P. Xie, M. Chen, and M. Q. Zhang, 2017 Stochastic fluctuations can reveal the feedback signs of gene regulatory networks at the single-molecule level. Scientific Reports 7: 16037. https://doi.org/10.1038/s41598-017-15464-9
Lu Y., K. Bohn-Wippert, P. J. Pazerunas, J. M. Moy, H. Singh, et al., 2021 Screening for gene expression fluctuations reveals latency-promoting agents of HIV. PNAS 118. https://doi.org/10.1073/pnas.2012191118
Palmisano L., and S. Vella, 2011 A brief history of antiretroviral therapy of HIV infection: success and challenges. Ann Ist Super Sanita 47: 44–48. https://doi.org/10.4415/ANN_11_01_10
Trachootham D., W. Lu, M. A. Ogasawara, N. R.-D. Valle, and P. Huang, 2008 Redox Regulation of Cell Survival. Antioxid Redox Signal 10: 1343–1374. https://doi.org/10.1089/ars.2007.1957
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