Despite improvements in prevention 7,000 new HIV infections occur daily in the world with a total of 33 million chronically infected. Antiretroviral therapy access is uncertain in many countries, and raises concerns even in the developed world. Life-long therapy is a huge cost, needs constant adherence and implies toxicities. Therefore, future research should focus on understanding the mechanisms allowing HIV persistence in viral reservoirs and development of new strategies to eradicate, or at least, control them for a drug-free remission. The year 2010 showed that the research community was ready to tackle the challenge.
Toulon, France—January 03, 2010–
HIV persistence is primarily due to latently infected long-lived immune cells where antiretroviral drugs do not act. They are mainly CD4+ T lymphocytes but other lineages, like stem cells or macrophages, could also be involved. It is highly likely that unrecognized cell reservoirs exist. As one -or a few- residual cell(s) harboring replication competent HIV will 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.
It is an important debate: if it could be proved that low levels of HIV replication persist during therapy, this would indicate that more than a triple drug combination is required to be effective. However, most intensification trials failed to demonstrate any effect of adding one or two new antiretrovirals to the regimen in terms of low levels 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 hides, in particular in the gut.
As residual HIV disease on effective therapy only concerns 1 to 10 million cells in the whole body, current biological tools reach their limits to show a change during reservoirs targeted strategies. Outgrowth assays are not sensitive enough; cell-associated proviral DNA is a rough estimate, and viremia at the copy level is subject to variations. Our ability to quantitate 2-LTR circles in infected cells and integrated viral DNA will certainly help. Tissues sampling access is also essential but meets ethical issues for invasive procedures in patients who are quite well.
There are currently three areas of research:
-Treat as early as possible: when antiretroviral therapy is initiated during primary infection (i.e. within a couple of weeks after contamination), up to 15% of patients achieve HIV drug-free remission when it is subsequently stopped.
-Purge HIV reservoirs: chemical compounds are selected to reactivate latent HIV on a background effective antiretroviral regimen, to deplete the reservoir. Several companies work on Histone Deacetylase inhibitors, compounds 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. Once re-infused in patients, these cells might reconstitute an intact immune system. Finally, encouraging proviral integration in cells by some peptides can lead to genome instability and cell death.
The year 2010 saw the report of the Berlin patient who was cured from HIV by a bone marrow transplant. It will probably remain an isolated case, but has boosted the optimism of the research community for a cure. If a sterilizing HIV cure is far away, current research is promising for a functional HIV cure. Let’s hope that important breakthroughs will come in 2011.
Alain Lafeuillade, MD
1208 av. Col. Picot
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