HIV Replenishes Viral Reservoirs During Therapy
When HIV infects the body, it establishes a key foothold in lymphoid tissue and can persist there, despite potent therapy. But HIV is not dormant in this viral reservoir; the virus continues to replicate, move between tissue compartments and evolve – even when it is undetectable in the blood.
HIV continues to replenish its viral reservoir in lymphoid tissue even when it can no longer be detected in the bloodstream.
This was the conclusion of a new international study – led by Northwestern University in Chicago, IL, and published in Nature – that provides an important new perspective on how HIV stubbornly persists in the body, despite powerful antiretroviral therapy.
Senior and corresponding author Steven Wolinsky, a professor in medicine and chief of infectious diseases at Northwestern’s Feinberg School of Medicine, says:
“We now have a path to a cure. The challenge is to deliver drugs at clinically effective concentrations to where the virus continues to replicate within the patient.”
The HIV (human immunodeficiency virus) weakens the immune system by destroying important white blood cells, called CD4 or T cells, that fight disease and infection.
As the HIV infection worsens, the immune system gets weaker and weaker and the person becomes more prone to opportunistic infection. Acquired immune deficiency syndrome (AIDS) is the final stage of HIV infection, when the body can no longer fight life-threatening infections.
There is no effective cure for HIV, although the availability of potent antiretroviral therapies means what was once a fatal diagnosis can now be managed as a chronic disease.
The Centers for Disease Control and Prevention (CDC) estimate there are over 1,218,400 Americans aged 13 years and older living with HIV, including 156,300 (12.8%) who are unaware they are infected with the virus.
Nowadays, combinations of powerful antiretroviral drugs can reduce HIV to undetectable levels in the bloodstream of most patients. But the virus can persist in pockets in lymphoid tissue in the body and quickly appears again in the blood when patients stop taking the drugs.
This suggests the virus persists in this reservoir because it either continues to replicate at low levels, it is able to survive in long-lived infected cells – or both.
As nobody had detected viruses with new mutations, and because patients on antiretrovirals do not develop drug resistance when the virus is gone from the bloodstream, it was thought the viral reservoir only contain long-lived HIV-infected cells in a dormant state – and no newly infected cells.
For their study, Prof. Wolinsky and colleagues sequenced viral DNA from infected cells sampled from the lymph nodes and the bloodstream of three HIV-infected patients before and during their first 6 months on antiretroviral therapy.
The results showed that the virus evolved over time – and was therefore replicating – but the mutations did not indicate it was developing drug resistance.
The team then developed a mathematical model to investigate how the virus might evolve during therapy without developing drug resistance.
The model showed that drug-sensitive HIV strains tend to dominate over drug-resistant strains in the presence of low drug concentrations. But the model also showed that as drug concentration rises, this changes and the drug-resistant strains begin to dominate. And at high concentrations, HIV cannot grow at all.
This finding highlights the importance of delivering effective antiretroviral drug concentrations into the lymphoid tissue compartments, note the authors.
Antiretrovirals that penetrate the lymphoid tissue compartments where HIV can persist and replicate will be a prerequisite to the elimination of the viral reservoir and, ultimately, a step toward a cure, they suggest.
Coauthor Angela McLean, professor of mathematical biology at the University of Oxford in the UK, who led the mathematical modeling, concludes:
“The study is exciting because it really changes how we think about what is happening in treated patients. It helps explain why some strategies that tried to clear the reservoir have failed.”
In November 2015, Medical News Today learned of another study that found effectiveness of HIV antiretroviral treatment in adults may be hampered by low levels of vitamin D. That research found that patients with sufficient levels of vitamin D recovered more of their immune function during therapy than patients with vitamin D deficiency.
Written by Catharine Paddock PhD