The Weird Story of the Berlin Patient

Written by Alain Lafeuillade

Friday, 08 June 2012 19:31

The Weird Story of the Berlin Patient

The only case of a possible sterilizing HIV cure has been challenged today at the 2012 HIV resistance workshop: the patient, actually, could still be HIV infected!

Eveybody knows the story of the "Berlin patient" (see, in particular, several articles and an interview of him on this website).
As an American citizen he flew back to San Francisco 2 years ago after havin being "cured" in Berlin by Dr Hutter (first publication in the N Engl J Med in 2009, last one in Blood in December 2011).

But it came like a thunder this morning when Dr Steven Yukl presented his talk intitled "Challenges inherent in detecting HIV persistence during potentially curative interventions."
An enigmatic title that hides quite a weird story.
Note that coauthors of this abstract are: T Chun, MC Strain, J Siliciano, E Eisele, R Buckheit, YC Ho, JK Wong, MP Busch, G Hütter, DD Richman, RF Siliciano, SG Deeks.
Actually, most of these people repeated several experiments on this patient blood plasma, blood cells and rectal biopsies...
And the facts are these:
"A large volume apheresis was performed and 9 billion PBMCs evaluated for the presence of replication-competent virus. All wells were negative for HIV p24, indicating that the frequency of replication-competent HIV was therefore estimated to less than one infected cell per 1.4 billion CD4+ T cells. A repeat experiment in a second laboratory confirmed these findings. Using a variety of assays and approaches, very low levels of HIV RNA were intermittently detected in plasma, although sequence analysis of these variants were different from each other and different from those present before the transplant. Digital PCR for HIV DNA was negative for 1 copy per 2 million cells with a 95% confidence limit of less than 1.9 copies per million cells. Collagenase-digested rectal biopsy-derived cells were positive for very low levels of HIV DNA but not RNA; no sequence for confirmatory studies could be obtained. HIV antibodies levels were low and declined over the course of approximately 18 months."
Data were also presented showing that although this patient remained HIV seronegative, he still has antibodies again HIV at a very low level of detection, below the cutoff of current commercially available ELISA tests.
These data raise several questions that are not addressed in the abstract conclusion: "Although the subject has had intermittent evidence for HIV persistence in some assays in some laboratories, the extremely low levels of virus which were detected, while pushing the limits of sensitivity and specificity, and the inability to match sequence with the subject’s pre-therapy virus make it impossible to conclude that the subject remains HIV infected."
First, is that only a matter of PCR contamination or variability of tests at such low levels. I personnaly have serious doubts about this argument because Deeks group did not even mention this variability at last CROI when they reported that Disulfiram was able to exhibit an anti-latency effect, based on very small blips!
Second, it is strange to see that the different research teams do not have any data on soluble markers of inflammation, HIV in semen, or the tropism of the circulating strains...That is ongoing they answered.
Then, there are 2 other alternative explanations to this viral persistence during a "cure": one, the patient has never been cured and is a chimera, second, he has been cured but reinfected. In this direction goes the observation that rectal HIV DNA was negative when he was in Berlin, and now is positive. Also goes the fact that different circulating viral strains were isolated.

A terrific story if there is. It was amazing to see that Steve Yukl, the virologist who never met the patient was at the lectern without a bullet proof suit....and that Steve Deeks sat quietly at the back of the room, the one who currently follows the patient...

To be continued, like TV series say....

Key words: Berlin patient, HIV cure, HIV eradication

Last Updated on Friday, 08 June 2012 19:51

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Theo Smart 09.06.2012 (22:35:53)

Archival RNA from lysed cells?

This may be a dumb question, but is it possible that any RNA where reverse transcription was interrupted (by NRTIs) could persist in some cells, and be released into the bloodstream when those cells die or are lysed? If so, if it possible that these represent variants that were not in circulation at the time of the procedure? Or could these be the product of replicative imcompetent virus... essentially sterile virus?

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Theo F Smart 09.06.2012 (22:57:52)

CCR5 delta 32 mutant stem cells

Or rather than re-infection, could few old reservoirs with archived virus perhaps from super-infections that never got very far, be reactivated from time to time. And of course the cells derived from the CCR5 delta 32 mutant stem cells transplant continue to block any productive infection.

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Barasa Situma 10.06.2012 (13:29:33)

HIV Reserves

I think the patient is cured.Low levels of detection of that magnitude only means some long live infected cells perhaps not even characterized might be present, but of course these are incapable of propagating the virus in any way and will eventually be cleared.Low level of antibodies is probably the norm for survivors of any infection.
I have already worked out a cure for HIV based on elimination from bone marrow reserve, but I cant publish because it sounds too speculative and I lack the technical capacity to validate my theories. To see some of my files log on http://www.ncbi.nlm.nih.gov/pubmed/22267945 or e-mail me at barasa_simon@ya hoo.com for newer files

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Cecilia Graziosi 12.06.2012 (16:18:17)

Contamination

"...very low levels of HIV RNA were intermittently detected in plasma, although sequence analysis of these variants were different from each other and different from those present before the transplant."

Isn't this just contamination? I did not understand the argument against this possibility.

Since variants are all different from each other, one should assume the occurrence of several events of reinfection and this sounds less likely.

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Irving Langmuir 13.06.2012 (07:19:36)

Maybe next time you reinterpret someone else's research to come to a radically opposite conclusion of the authors themselves you can release a television advertisement and call an international press conference with confetti and balloon animals, eh? This is a joke, I'm not even a doctor and it's clear to me this guy is making a fool of himself. The chances of the signals they're seeing not being contamination are miniscule.

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James 14.06.2012 (22:20:34)

appropriate control

One would need to evaluate an equivalent 9 billion cells from an equally sexually active HIV negative individual who is consider uninfected to make a legitimate comparison. RNA which is not contained within the protein coat of the virus or the protection of a cell is rapidly digested via RNAses. The environment is essentially a sea of DNA and sequence fragments that remain integrated into cellular DNA may contain HIV sequences. In designing Nucleic Acid diagnostic devices we often found the presence of sequences at very low levels of sensitivity (eg. one or two copies/ ml of sample) which was not considered signs of infection. We were always required to compare them to the existing standard criteria of diagnostics to determine clinical significance. My guess is there are many people who are considered uninfected by HIV who have sequences present in their tissues and cells, Professor Duesberg's hypothesis notwithstanding .

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Barasa Situma 16.06.2012 (12:05:08)

Thank you James

You got it! It is inconcievable that such a widely disseminated infection as HIV would leave no vestiges upon radical cure.The point is, if the body was able to bring trillions of virus particles to control and total removal of disease, how then can it fail to deal with very small numbers of persistors? Re-infection could probably occur only if the circumstances of his body changes

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Gerard 28.06.2012 (04:58:15)

Contaminations

The writer brought up a very important point. If the positive tests were all contaminated, why was there no contamination for the last 5 years of the experiment? Why the sudden blips in 3 indepedent labs? Obviously something has happened. Obviously, some of the existing cells have at least pieces of DNA integrated into its genome and is multiplying. All it takes is just one cell with a full hiv sequence in it. They are probably siting in the brain waiting and quietly multiplying little by little.

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