Why can HIV remain latent in the body?


View:1027 Time:2018-03-09



HIV, short for human immunodeficiency virus, is a reverse retrovirus. HIV is transmitted by blood contact (like sharing a needle or syringe), sexual behavior, mother-to-child. Daily contacts with infected patients do not infect HIV, such as shaking hands, hugging, coughing or sneezing, sharing utensils, etc.


Once HIV enters into the body, it attacks the body's immune system, especially CD4+ T cells, which help the immune system fight infection. If untreated, HIV leads to a progressive reduction of CD4+  T cells, thus resulting in an imbalance between the ratio of CD4+  T cells and CD8+  T cells, which damages the immune system, providing more opportunities for infections or infection-related cancers to invade the body. This usually causes a condition called AIDS (Acquired Immune Deficiency Syndrome).












Figure1  AIDS Red Ribbon and HIV Transmission Routes
(sourcing: https://sojo.net/articles/achieving-aids-free-generation-healing-international-village)


AIDS is a global public health problem that seriously threatens human life. Scientists have been working on studying HIV to find out effective therapies for it. Current drugs can effectively control the active viruses after decades of efforts but still can not wipe out those that hide in the "Latent Reservoir".


Like other viruses, HIV raised in the body attacks the cells in the immune system and replicates itself by exploiting cell's machinery, proliferating more active viruses. However, some HIV-infected cells remain a resting state and stop making active viruses. These infected cells are known as Latent HIV Reservoir.


Previous studies have demonstrated that HIV lurks "not by accident" but as a deliberate "survival strategy". It overlays its base by generating active and latent infections to survive in a turbulent environment.


There are two research on latent HIV that potentially provide therapeutic strategies or treatments for HIV.


1.ACSS2 plays a key role in the regulation of HIV transcription and latency

2.A new angle of attack drives cellular HIV-reservoirs to self-destruction



ACSS2 plays a key role in the regulation of HIV transcription and latency

HIV is hard to battle, in part because the virus can lie dormant, or latent, in infected cells for a long period of time. Through this mechanism, HIV evades the toxic effects of therapies and the attacks of the immune system. Disrupting HIV latency is, therefore, a potential therapeutic strategy.


HIV latency is regulated by an epigenetic mechanism called histone crotonylation that controls gene expression, according to a new study (HIV latency is reversed by ACSS2-driven histone crotonylation) published in the Journal of Clinical Investigation (JCI) on February 19, 2018. This study suggests that histone crotonylation can be targeted for HIV eradication.


Enormous progress has been made in improving HIV treatment and reducing HIV deaths. Antiretroviral therapy (ART) are medications that treat HIV. These medicines are called antiretroviral drugs accordingly. ART allows many HIV-positive people to live longer and healthier lives. Additionally, this therapy also helps prevent transmission of HIV. Now, HIV infection is largely a chronic disease. But, ART drugs cannot kill or cure the virus. There are still a large number of people living with HIV.


Why can HIV remain latent in host cells? It is a long-standing mystery. If scientists can resolve this mystery, they may be able to find approaches to kick and kill HIV. A cure for HIV/AIDS has long been an important goal of medicine.


Studies have shown that viral latency is epigenetically regulated, but the regulatory effects of epigenetic modifications on transcription and latency of HIV are not fully defined. In the new study, Dr. Satya Dandekar from UC Davis and collaborators demonstrated that the epigenetic mechanism histone crotonylation is involved in the establishment of HIV latency. In addition, they confirmed that reactivation of latent HIV was achieved after the induction of histone crotonylation through increased expression of ACSS2.


ACSS2, short for acyl-CoA synthetase short-chain family member 2, is an enzyme that is involved in lipid metabolism and energy generation. Given that HIV infection is often associated with particular unbalances in lipid levels, ACSS2 may be a potential target for treatments of HIV.


Findings of the new study confirm that ACSS2 plays a key role in the regulation of HIV transcription and latency. The researchers concluded that their study "links the HIV/SIV infection–induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication."


Furthermore, combining histone crotonylation with other mechanisms that reactivate HIV may be a more effective approach to disrupt HIV latency. This approach would help scientists find a cure for HIV in the future.



A new angle of attack drives cellular HIV-reservoirs to self-destruction

Research on AIDS has never stopped. A recent study on HIV proved that a long non-coding RNA (lncRNA) called SAF is significantly upregulated in HIV-infected macrophages. Although previous studies have found that SAF can prevent apoptosis or self-destruction. lncRNAs are genetic coding elements that are not directly converted to the protein itself, but regulating the rise or fall of genes, and are also called "main regulators of cellular pathways."
To demonstrate that SAF protects HIV-infected macrophages from death, the team blocked the effects of SAF with another non-coding RNA called small interfering RNA (siRNA), which is effective in degrading SAF.


In all SAF-silent health, infection, and bystander (healthy cells exposed to the HIV) macrophage population, the team observed that HIV-infected cells suddenly self-destructed, while healthy and bystander cells were not harmed. This suggests that when a cell is infected with HIV, the virus alters the expression of lncRNAs in that cell. This may explain why the bystander cells exposed to HIV virions but not actually infected by them do not have the same response.


This finding provides a new perspective for curing HIV: selectively destroying cells that continue to infect. The researchers plan to conduct drug testing on compounds that drive HIV-infected cells into programmed cell death. Now the team is working on finding SAF inhibitors, but will also look for other molecules that effectively eliminate latent reservoirs through other mechanisms.



Conclusion:

HIV is a serious health problem worldwide. HIV attacks the body's immune system, and over time, it may weaken the immune system. As a result, patients are susceptible to health problems, such as cancer. When HIV remains latent in host cells, the virus is nearly impossible to target with ART drugs. So, scientists are trying to disrupt HIV latency in order to make the virus to be attacked by therapies as well as immune responses.


Furthermore, the prevention of HIV is also comparatively important. After all, prevention is easier than cure. Therefore, the recommendation is to use condoms or reduce the sexual partners, avoid drug use by intravenous needle sharing, and prohibit illegal blood transfusion.


 
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