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HIV Reservoirs Cure or Strategies to Control Them in the Face of HIV Persistence
Despite improvements in prevention, more than 7,000 new cases of HIV infection occur daily in the world with more than a total of 33 millions individuals chronically infected. Access to antiretroviral therapy in uncertain in many parts of the world, and raises concerns in developed countries. Life-long therapy implies major economic costs, permanent adherence and management of toxicities. Therefore, future research should focus on understanding the mechanisms that allow HIV persistence in viral reservoirs and development of new strategies to eradicate, or at least, control them in the way of a ‘drug-free’ remission. The year 2010 showed that the research community was ready to tackle the challenge.
HIV Persistence in Viral Reservoirs
HIV persistence is primarily due to latently infected long-lived cells of the immune system in which antiretroviral drugs do not act. They are in majority CD4+ T lymphocytes but other lineages, like stem cells or macrophages, could also be involved. It is also highly likely that other unrecognized cell reservoirs exist. As probably one (or a few) residual cells harboring replication competent HIV would be sufficient to rekindle infection, this is a daunting challenge. In addition, anatomic reservoirs like the brain represent sanctuaries for HIV where current antiretroviral therapies might not be totally effective due to diffusion issues.
Ongoing HIV Replication
This issue is a hot debate in the field, because if it could be proved that low levels replication persist on therapy, this would mean that we need more than a ‘triple drug’ combination to be effective. However, most intensification trials failed to demonstrate any effect of adding one or two new antiretrovirals to the combination on the low level persistent viremia below 50 copies/ml. In one trial, adding an HIV integrase inhibitor transiently increased the number of 2-LTR circles in one third of patients, a proof of ongoing viral replication. Finally, almost nothing is known about persistent HIV replication at the tissue level, where HIV source resides, in particular in the gut.
New Tools to Monitor HIV Reservoirs
As residual HIV disease on effective therapy only concerns 1 to 10 million(s) cells in the whole body, current biological tools have reached their limits to show any changes during a reservoirs’ targeted strategy. Outgrowth assay are not sensitive enough; cell-associated proviral DNA is a rough estimate, and viremia at the copy level remains insufficient. Our ability to now quantitate 2-LTR circles in infected cells and integrated proviral DNA will certainly help. Tissues sampling access is also important but meets ethical issues for invasive procedures in patients who are quite well.
Prospects for HIV Reservoirs Control or Eradication
There are currently 3 ways of research:
-Treat as early as possible:
When antiretroviral therapy is initiated during primary infection (i.e. within the first weeks after contamination), up to 15% of patients can achieve a drug-free remission when therapy is subsequently stopped.
-Purge the HIV reservoir: Chemical compounds are selected to reactivate latent HIV under a background of effective antiretroviral therapy, with the aim of depleting the reservoir. Several companies try to isolate Histone Deacetylase inhibitors, drugs that have been shown capable of reversing latency in vitro. If this strategy proves to be able to reduce the HIV reservoir size, it is highly likely that it will have to be complemented by an immunologic intervention, to contain the very last reservoir cells. Controversies are growing with this approach as some researchers think it could put the brain reservoir beyond control and cause more harm than good.
-Induce a sabotage of HIV infection:
This promising strategy tries to induce flaws in the HIV infection process. Chemical compounds can induce lethal mutations in the HIV genome, leading to viral ablation. Gene therapy can create CD4+ cells resistant to HIV, as they lack the CCR5 co-receptor expression. These cells can be re-infused in patients, helping to reconstitute an intact immune system. Finally, encouraging proviral integration in cells by some peptides would lead to genome instability and cell death.
The year 2010 has seen the report of the ‘Berlin’ patient who was probably cured from HIV by a bone marrow transplant. Although it will probably remain an isolated case, it has boosted the optimism in the research community for a cure. If a ‘sterilizing HIV cure’ will certainly need more time, current research is promising for reaching a ‘functional HIV cure’. Let us guess that important breakthroughs will come in 2011.
Alain Lafeuillade, MD
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