HTB

Update on the Berlin patient

Richard Jefferys. TAG

Eleven years ago, a plethora of media stories described the case of “The Berlin Patient,” an individual who received antiretroviral therapy during acute HIV infection and subsequently maintained viral load below 50 copies for many years after stopping treatment. [1]

This individual turned out to possess the HLA B*57 allele which is strongly and consistently associated with long term non-progression of HIV infection, and it remains somewhat uncertain if he might have become an elite controller even in the absence of any treatment. At the recent Keystone HIV pathogenesis meeting in Colorado, Guiseppe Pantaleo described another similar case, but in this instance lacking known favorable HLA alleles.

The individual — dubbed patient 1010 — was a participant in one of Pantaleo’s studies of acute infection treatment. The protocol compared ART alone to ART together with a short course (8 weeks) of treatment with cyclosporin A (CSA); there were 59 individuals in the trial, ten who received ART and 49 assigned to ART + CSA. Results were  published in the Journal of Clinical Investigation in 2002, and showed that receipt of CSA was associated with significantly higher CD4 counts, a difference which Pantaleo reported has been maintained out to four years of follow up. [2]

Patient 1010 enrolled in the study in March of 1999, approximately two weeks after becoming HIV-infected, with a baseline viral load of 26 million copies. He was randomised to receive ART + CSA and was adherent until stopping ART on December 31, 2000. Surprisingly, viral load rose to just 63 copies two weeks later, and has remained below 50 copies without further treatment during the subsequent eight years of follow up; his CD4 count has stayed stable at around 2,000. Pantaleo noted that he is wild-type for the delta32 CCR5 mutation and also lacks any of the major HLA alleles that have been associated with elite control (his class I HLA types are A*0301, B*0702 and B*4002).

Pantaleo went on to describe the profiles of HIV-specific T cell responses in patient 1010. Around 3.5% of CD8 T cells are HIV-specific, targeting Gag, Vif, and Env proteins. An unusually large proportion of these cells (~80%) produce both IL-2 and interferon gamma, and they have what Pantaleo describes as a “massive capacity” for proliferation upon stimulation with antigen, the highest his lab has ever seen. The proportion of cells making IL-2 is also far greater than Pantaleo has previously seen in studies of untreated elite controllers. The differentiation profile of the HIV-specific CD8 T cells equates with a quiescent central memory phenotype, with over 80% of the cells expressing CCR7, CD127, CD27 and CD28.

Based on this anecdotal case, Pantaleo provocatively hypothesised that the ideal immune profile associated with virological control may be the “quiescent, non-effector” CD8 T cell response he has documented in patient 1010. It appears that the virus is so robustly controlled in this individual that HIV-specific T cells are hardly ever encountering antigen. Pantaleo mentioned that Tae-Wook Chun from NIAID has looked for HIV in the patient and found only 1.7 copies of HIV DNA per microgram of genomic DNA, and 11 copies of HIV DNA per million peripheral blood mononuclear cells (PBMC). Chun has calculated that there are approximately 0.0027 infective units of virus out of 360 million CD4 T cells sampled, the lowest he has ever documented. HIV DNA levels were extremely low even in the gut.

The case adds to a number of reports suggesting that a very small proportion of individuals who interrupt ART after being treated for acute infection can maintain control of viral load for variable periods of time. It is generally unclear if these individuals might have gone on to become elite controllers without treatment, but the high viral load and lack of protective HLA alleles in Pantaleo’s patient appear to argue against this possibility. The individual is also clearly an outlier in terms of the extremely low levels of HIV DNA that are detectable and the strong proliferative capacity and IL-2 producing potential of his HIV-specific T cell responses. The duration of time off therapy — over 8 years — is also unusual. Whether CSA may have somehow contributed to this salutary outcome is unclear and almost certainly unanswerable without additional studies.

Although it’s clearly possible — some might say likely — that anecdotes such as this one reflect some rare and unknown trait possessed by the individuals involved, they might also be hinting that prolonged and robust immune control of HIV is an achievable goal.

Comment

There are many well-documented cases of patients who are untreated who suppress viral load and do not progress for many years. However, these patients may start to progress subsequently. So, there really isn’t much evidence yet that ART+CSA actually had any impact on his outcome.

Source: TAG Basic Science Weblog. (15 Apr 2009). http://tagbasicscienceproject.typepad.com

Reference:

  1. http://www.nytimes.com/1998/06/21/magazine/the-berlin-patient.htm l?pagewanted=all
  2. http://www.jci.org/articles/view/14522

Links to other websites are current at date of posting but not maintained.