Tuesday, April 30, 2013

HIV Reservoirs and Viral Eradication

The advent of combined antiretroviral therapy (cART) more than 15 years ago has dramatically changed the outcome of HIV infection from a deadly to a chronic disease. However, patients still experience problems of compliance, resistance, toxicity and cost. Furthermore, these therapies are not available worldwide, in particular in poor-resource areas where most of HIV-infected patients live.

If plasma viremia can remain undetectable in the majority of patients taking everyday cART, HIV remains in hidden reservoirs allowing viremia to rekindle within a few weeks each time therapy is stopped.

Over the past few years major advances have been made in understanding the nature and persistence mechanisms of these HIV reservoirs. It is currently believed that HIV remains latent in some memory T cells, which have a very long life span and not affected by cART. This reservoir of a few million cells in the body is considered as the major obstacle towards HIV eradication in treated patients.

However, if a decade ago almost nobody dared to speak of curing HIV infection, scientific advances have allowed developing potential strategies for a cure, some of which have already reached clinical trials.

This renewed optimism has been spurred by 3 clinical observations:

1-The Berlin patient:

This case has been widely reported. It involves a man who developed acute leukemia during the course of HIV infection and received a bone marrow transplant from a donor with a genetic mutation that protects against HIV infection. With now more than 5 years of follow-up, this patient is off cART and has not experienced viremia rebound or immune deterioration.

2-The Mississippi child

Reported in early 2013, this case was born from an HIV-infected mother who was not followed, and consequently not treated, for her infection. HIV infection was documented at birth in the child and cART started as early as 31 hours after delivery. One year later, the mother and the child were lost of follow-up. When they showed up again in the clinic, the child was 23 months of age and had stopped cART for at least 5 months. Unexpectedly, no detectable viremia was found in the child blood by using the most sensitive assays.

3-The VISCONTI cohort

This French cohort (VISCONTI is for "Virological Sustained Control after Treatment initiated at acute Infection") has collected 14 patients who were treated very early after HIV infection, for an average duration of 3 years, and still have undetectable viremia despite cART cessation for an average duration of 7 years. Although they still harbor potentially replicating HIV in their body, the virus remains under control without drugs. The mechanisms of this "functional cure" remain unclear, but this situation could concern 10-15 percent of patients treated at acute infection.

What the first 2 cases show is the limits of our current biological tests to define a sterilizing cure. This situation would be the total elimination of HIV from an infected person. However, the majority of HIV DNA integrated in cells is defective and unable to replicate. Therefore, a sterilizing cure is not necessarily a situation where traces of HIV cannot be found. This is the case in the Berlin patient and the Mississippi child where, using the most advanced technologies, traces of HIV could be found, in some tests, but at the limit of detection of the assays.

These observations are seminal in the search of an HIV cure. Understanding the mechanisms at play can be of major importance for the 34 million people living worldwide with this virus.

For 10 years now, the "International Workshop on HIV Persistence, Reservoirs and Eradication Strategies" has attracted scientists from all around the world to work on these issues.

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