A new study showed a method to detect T cells where HIV hides. This could allow the development of drugs meant to flush out dormant viral particles.
The innovative technique to identify T cells used by HIV to hide was discovered by scientists at The Wistar Institute, a US research institute. Their technique involves sugar-based signature detection to track down hideouts of HIV. The method could boost the efficacy of antiretroviral drugs. They published their findings in the journal Cell Reports.
The Steady Decline in HIV/AIDS Deaths
HIV or human immunodeficiency virus has claimed millions of lives worldwide. It is the main cause of acquired immunodeficiency syndrome or AIDS. Until now, HIV/AIDS is a global health challenge due to the lack of a cure or functional vaccine. Before treatment was developed, the disease stirred confusion, panic, and social discrimination, especially among the LGBT community. Fortunately, scientists found a way to manage the illness.
The management of HIV/AIDS is called antiretroviral therapy or ART. It involves up to five kinds of antiretroviral drugs to significantly slow down the disease. These drugs substantially increase the life expectancy of HIV patients. The active ingredients cripple the replication of the virus inside the body. This results in one critical effect: reduce the risk of transmission to others. Because the virus is suppressed, an HIV-positive person has a low chance of spreading the virus to others, compared to a person who is not treated with ART.
Still, HIV patients are advised not to take risky behaviors to protect themselves from catching another strain or giving others the virus. While HIV-negative individuals are at risk of contracting the virus are recommended to take HIV pre-exposure prophylaxis (PrEP). If taken regularly, PrEPs can greatly reduce the odds of contracting the virus from others. But these drugs are no longer effective in people who already contracted the virus.
According to Statista, a German portal for statistics, the death toll from HIV/AIDS continued to show a decline in 2018. In 1990, the estimated death was equal to 290,000. This might represent a significant number of people who have not developed the symptoms of AIDS. By 2004, the global death toll surged to 1.7 million. It showed how many people in several years were infected by the virus, whether aware or not. It also reflected how many people were not treated with ARTs. But in 2018, the death toll dropped to 770,000, a result of increased access to HIV medications.
As of 2019, around 38 million people were living with HIV and 25.4 million HIV-positive individuals were under ART. About 1.7 million new HIV cases and 0.69 million AIDS-related deaths were reported.
New Sugar-Based Signature to Find HIV Hiding in T Cells
Despite the efficacy of ARTs against HIV, none of the existing antiretrovirals can eliminate the virus completely. They can only delay the disease progression to a certain extent, enough for the patient to live a relatively normal life. But within the treatment period, the patient is at risk of side effects caused by ARTs. Thus, HIV research has not stopped to find a cure or vaccine.
The reason why ARTs are ineffective in clearing HIV in the human body is due to the unique mechanisms of the virus. Aside from mutations, the virus can hide inside infected cells and lay dormant until the effects of ART wane. So, when a patient decided to miss or stop their treatment, the virus rebounds and sometimes becomes stronger. This leads to regimen adjustments to stop the disease from progressing. Hence, some HIV patients are taking more than three antiretrovirals.
At Wistar, scientists may have discovered a way to find T cells used by HIV for hiding. It is a sugar-based signature detection tool to find hiding viral particles. The identification of the viral hideouts is led by a process called fucosylation. In fucosylation, a sugar molecule called fucose is attached to proteins present on a cell's surface. It is known to be important in T cell activation. The process has been found quite persistent in HIV-infected T cells.
"With recent advances that we are making in the fields of glycobiology and glycoimmunology, it has become clear that the sugar molecules present on the surface of immune cells play a critical role in regulating their functions and fate. However, the relevance of host cell-surface glycosylation in HIV persistence remained largely unexplored, making it a 'dark matter' in our understanding of HIV latency. For the first time, we described a cell-surface glycomic signature that can impact HIV persistence," said Dr. Mohamed Abdel-Mohsen, the corresponding author of the study and assistant professor in The Wistar Institute Vaccine and Immunotherapy Center.
In the study, the team revealed the two groups of persistently infected T cells. The first group is called the silent HIV reservoir, wherein infected cells do not produce the viral RNA. The second group is called the active HIV reservoir, wherein infected cells do produce low levels of viral RNA. If a drug could target both, it might be the cure people are looking for. Scientists used a primary cell model of HIV latency for their research. This allowed them to characterize the glycomes on the cell surface of infected T cells.
The cell samples were isolated from HIV-positive patients being treated with ART. On top of fucosylation expressed by the cells, another expression was detected from a specific fucosylated antigen known as Sialyl-LewisX or SLeX. This expression was identified with persistent HIV transcription in vivo. Infected T cells with that expression exhibited higher levels of pathways and proteins associated with viral transcription. The expression would be greater during exposure to ART. That pattern was not observed in silent HIV reservoirs. The difference provided a key distinguishing mark between the two groups. And finally, the virus promoted the glycomic changes in active HIV reservoirs.
In cell studies, the high expression of SLeX is usually found in certain cancer cells. The expression lets malignant cells to spread to other parts of the body. HIV uses the same expression to traffic itself between tissues and the blood. It explains why ARTs fail to completely clear the virus because HIV has a definitive method of escaping.
The study findings warrant further studies into fucosylation in HIV. If it can be targeted, it will enhance the efficacy of ARTs in clearing HIV reservoirs.