The Brain HIV Reservoir in Eradication Trials
An interview of Janice Clements and Avindra Nath, Johns Hopkins University, Baltimore, USA
In a recent editorial/opinion in the journal 'AIDS' (1), Janice E. Clements, Professor of Molecular and Comparative Pathobiology and Avindra Nath, Professor of Neurology and Neuroscience at the Johns Hopkins University in Baltimore, MD, call for a pause in HIV eradication trials before fundamental questions with regards to the biology of the virus in the brain are solved. Their fear is that the brain HIV reservoir could be put beyond control with such strategies. They kindly agreed to answer un couple of questions from us...
Q1: We have read with great interest the ‘Opinion/Editorial’ you recently co-signed in AIDS, could you explain why you are ringing the bell?
JC & AN: In light of the new research effort in HIV eradication, we wanted to provide a perspective about the impact on HIV infected cells in the brain. In order to purge cells that harbour latent virus, drugs are being tested that reactivate virus and eradication depends on the presence of anti-retroviral drugs to prevent spread of the virus. In the case of the CNS, the levels of many antiretroviral drugs is much lower than in the periphery and it is not known whether strategies designed for reactivation of latently infected cells in the periphery/prevention of viral spread will work in the brain.
In some HIV infected patients the virus enters the brain and establishes a reservoir in resident macrophages and astrocytes. Activation of the virus in these cells could lead to an influx of cytotoxic lymphocytes, leading to inflammation in the brain. Any inflammatory process in the brain may be injurious to neural cells. The brain as opposed to other organs resides in a tight bony compartment and cannot sustain any swelling without substantial injury. Thus, eradication efforts need to consider how such therapy will affect the CNS.
Q2: Several teams have announced the short-term initiation of ‘eradication trials’ using SAHA or Il-7, what are the exact risks in your opinion?
JC & AN: As discussed above, “eradication trials” must consider the impact of the drug used for virus activation as well as the level of anti-retroviral drugs in the brain. HIV infected patients may be at risk of developing an immune reconstitution syndrome, hence careful neurological and neuroradiologic monitoring of these patients should be considered. The investigators should also consider screening patients for neurocognitive abnormalities and exclude those who have such abnormalities.
careful neurological and neuroradiologic monitoring of these patients should be considered
Q3: In the ‘Berlin patient’ HIV was eradicated using an approach targeting CD4+ T cells and the brain was not a cause of relapse, could you comment on it?
JC & AN: We do not know if this patient had any evidence of viral reservoirs in the brain. In the absence of any virus in the brain, no effects would be expected. Further, while HIV may currently be undetectable in the periphery, it is very difficult to be sure a potential viral reservoir such as the brain is truly free of latently infected cells.
Q4: Actually, in your opinion, what knowledge is pre-required before moving to the ‘next eradication step’?
JC & AN: It is critical to develop reliable and sensitive markers of viral reservoirs/replication in the brain. We also need to develop a way of quantifying the viral burden in the brain. This will help us select patients most suitable for such viral eradication studies. If we were to develop sensitive indicators of lymphocyte activation in the brain, we could monitor them closely for any evidence of CNS-immune reconstitution syndrome and then treat them before they develop significant brain injury.
1-Ref: Nath A, Clements JE. Eradication of HIV from the brain: reasons for pause. AIDS. 2010 Dec 14. [Epub ahead of print]
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Key words: hiv brain, hiv eradication, hiv reservoir, hiv reservoirs