HIV-infected people who are treated long-term with antiviral drugs may have no detectable virus in their body, but scientists know there are pools of the virus hiding there, awaiting the chance to emerge and wreak havoc again. Since scientists discovered these latent pools, they have been trying to figure out if the remaining HIV is the cause of or caused by increased activation of the immune system.
A group of investigators from Massachusetts General Hospital (MGH), led by Dr. Rajesh Gandhi of the MGH Division of Infectious Diseases, believe they have solved that mystery.
In work published in the journal PLOS Pathogens, they report that pretreatment levels of the virus — that is, how much of the virus is in your blood when you start being treated for the infection — and inflammation are what determines how much of the virus is squirreled in latent pools.
That also reinforces the idea that the earlier patients seek treatment for HIV — even if they aren't feeling its ill effects yet — the better outcomes the patient will have. This might be tricky for some patients because while most people will develop flu-like symptoms within two to four weeks of an infection, not all will.
The new research emphasizes why getting an early diagnosis is critical. People who have unprotected sex and experience flu symptoms should see a doctor right away and be tested for HIV. Once a diagnosis is made, your doctor will start treatment with antiviral drugs immediately.
More than 1.2 million people in the US are living with HIV, but as many as one in eight of them doesn't know it — mostly young people who don't have symptoms or aren't aware their symptoms could be due to an HIV infection.
People with early infections — in those first critical two to four weeks — or who don't know they are infected, can still transmit the virus. Getting tested for HIV if you are sexually active or if you have unprotected sex can help catch an early infection, as well.
Gandhi and colleagues have just shown how important that may become to the course of the disease.
The Problem with Latent HIV Pools
Previous research has shown that the early phase of an HIV infection is anything but silent. During that time, the virus is replicating rapidly and as many as 50 billion viruses are produced in an infected person every day, even if no symptoms are experienced.
The virus attacks a type of white blood cell called CD4 T lymphocytes. Once inside the cell, it commandeers the DNA of the host's CD4 cells to make copies of the virus. The new viruses burst out of the CD4 cells, killing them in the process.
The loss of CD4 cells is considered to be the driving force for immune activation. White cells of the immune system express proteins like those measured in the study — HLA-DR, CD14, CD163, and CD38 — in response to the presence of the virus and death of CD4 cells. They also secrete chemicals like interleukins and TGF-ß that signal the immune system to respond.
People infected with HIV can be successfully treated by taking combinations of different types of antiviral drugs that work at different steps of viral infectivity and replication. The treatment is successful when virus levels drop and become undetectable, but the virus usually is still present, hiding out in latent reservoirs.
The virus stays hidden in many places throughout the body, including in the brain, lymph nodes, blood, and the digestive tract.
And that's the problem. In some people, the latent virus may become active again, usually in response to infection with other viruses, nerve trauma, physical and physiological changes (like fever, menstruation, and exposure to sunlight), and immunosuppression (as in cytomegalovirus disease).
Finding Hidden Viruses
The scientists studied plasma and blood samples from HIV-infected individuals before they started antiviral treatment and after one, four, six, and 15 years of treatment.
By the one-year time point, the viral levels of everyone in the study were undetectable by standard laboratory testing. The average time the levels stayed undetectable was seven years, though some patients had undetectable levels for more than 10 years.
The scientists looked for HIV genetic material as a more sensitive way to find tiny amounts of hidden virus. This way, they could see how much of the virus was hiding, even when the blood levels were undetectable with traditional testing. They found those levels dropped the most over the first four years of antiviral treatment but also continued to decline over the following years.
They found that levels of HIV virus correlated with immune system activation in pretreatment samples, but not after antiviral treatment was started. Levels of immune system proteins — such as interleukin 6, HLA-DR, and CD14, CD163, and CD38 — associated with white blood cells were the indicators of immune system activation. The measures of immune system activation stayed elevated even once the virus became undetectable.
Gandhi concluded that early activation of the immune system that occurs before treatment continues even after people are treated to the point where the virus is no longer detectable. The pretreatment amounts of virus and amounts of inflammation — created by activation of cells of the immune system in response to the viral infection — were what determined the levels of virus that persisted in the body.
Sometimes, an illness or surgery means that a patient has to stop taking their medication. The drugs themselves can cause pancreatitis and other gastrointestinal disorders that force the medication to be discontinued until the patient's condition resolves.
If a patient stops taking their antiviral drugs, the HIV that hangs out in residual pools in the body can become active again and increase to detectable levels in two to three weeks. Scientists believe that reducing the number of these hidden cells could slow that viral reactivation rate.
Even those people who don't have an active infection again may still have serious ill effects. HIV-infected people of all ages have higher rates of heart attacks than people without HIV. Cardiac problems in HIV patients are thought to be due to increased plaque formation from chronic immune system activation and inflammation.
That's why finding out that pretreatment amounts of virus and levels of immune activation are what determines the amount of latent virus are very important revelations. If early treatment can help dampen viral replication before it gets too great and help reduce immune activation, that may lead to fewer later breakthrough infections and fewer health consequences.
The new research by Gandhi and colleagues has pointed us to the importance of that early time in HIV infections and highlights its importance in the long-term outcome of those infections.
This suggests that diagnosing HIV and starting antiretroviral therapy as soon as possible may prevent the elevated immune activation that can lead to health problems, such as heart disease.
New strategies to reduce the immune activation, combined with early administration of antiviral therapy may help reduce HIV infections beyond undetectable levels, all the way to viral elimination.
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