Dormant Proviruses Major Complication In Fighting Against HIV/AIDS

Dormant Proviruses Major Complication In Fighting Against HIV/AIDS

The cure to HIV has a major hurdle. It’s the large pool of dormant, replication-competent proviruses that have penetrated the very cells necessary in assisting in the organization of the body’s immune response.

While there are several barriers, it’s the latency issue that poses to be the biggest puzzle. Latency is the calm phase where proviruses wait for the moment to activate and start their attack on the body’s immune system. What is a provirus? It’s a sedentary virus a cell harbors. For HIV, the cells offer the provirus a safe haven to stay. These cells are called CD4+ T cells.

During this phase, proviruses successfully hide from the immune system and any antiretroviral drugs a person may be taking. Just these two factors alone make it hard to solve the HIV enigma.

Johns Hopkins University professor of medicine Dr. Robert F. Siliciano has been researching the HIV reservoir in the hopes of understanding it for more than 20 years. With help with collaborators from the University of California, San Francisco and Baltimore’s Howard Hughes Medical Institute, they highlighted a prominent point: while numerous CD4+ T cell subpopulations protect dormant proviruses, they don’t have a high inducibility of HIV-1 proviruses under investigational conditions.

According to the investigators, the key way to find a cure to solve the HIV latency issue.

Siliciano said latency might be the result of no host factors necessary with HIV gene expression. He said these epigenetic changes could lead to additional silencing of HIV gene expression that could cause HIV to go deeper into latency.

To get a better understanding of how confusing the pool of latent proviruses are, his group looked closer at antiretroviral therapy and noted it has the ability to block HIV from replicating in patients infected with the virus and prevent an immunodeficiency among people who take their medications as prescribed.

However, if treatment is halted for any reason, within weeks, the virus begins its replication process all over again, and the body is bombarded with new viruses due to the latent HIV proviruses that hid themselves from being destroyed.

Siliciano and his team said the research shows an increase in HIV-infected CD4+T cells is a huge factor in the latent reservoir. He said these intact HIV-1 proviruses are distributed evenly across the subsets of the CD4+ T cells, effector memory T cells and transitional memory T cells.

The worldwide HIV/AIDS pandemic began around 40 years ago, and it still a major public concern today as it was then. The infection is the result of a retrovirus, an RNA pathogen that contains an enzyme that can change the viral RNA into DNA when it invades the host cells. When this happens, the HIV DNA is able to insinuate itself into the host’s chromosomal DNA.

According to the World Health Organization, since the early 1980s, when HIV/AIDS was first discovered, there have been 75 million people infected with the disease, with 32 million people dying from it. While antiretroviral drugs can keep control over the infection, the viral latency phenomenon keeps the disease from being wiped out entirely by them.

While other viruses need the latency to survive, HIV needs it to help with the replication process, which is disturbing.

Siliciano said some viruses, such as the herpes virus family, need the latency to avoid the immune system response. However, HIV can avoid the immune response by constantly and quickly replicating itself in people who have not begun treatments.

Ongoing research is being done to cure the infection even in spite of the recent setback to create an HIV vaccine. A South African clinical study – the HVTN 702 trial – was called off because it failed to prevent new infections.

Siliciano said the experimental work he and his team are doing is to learn if the provirus of HIV goes into a deeper latency sate so that the cell can proliferate without generating any viral proteins. If so, then it could let the virus escape any immune clearance. He said the team used stimulation viral outgrowth assay to culture the cells. If the T-cells are activated, then it’s possible to reverse the latency.

Mark Riegel, MD
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Dormant Proviruses Major Complication In Fighting Against HIV/AIDS

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