Following Paula Cannon, Carl June from the University of Pennsylvania gave an update on the use of the same technology to modify CD4 T cells that are extracted from individuals with HIV using apheresis, expanded and modified in the laboratory, and reinfused into the same individual. Previous presentations of data from these phase I trials has generated considerable excitement, because the proportion of modified CD4 T cells persisting in the blood and gut of participants far exceeds the extremely modest levels obtained with prior gene therapies. Significant CD4 T cell count increases have also been documented up to nine months of follow up. Unusually, CD4:CD8 ratios have also improved from an average of 0.5 at baseline to 1.5 at last analysis; this type of improvement is rarely observed as a result of ART, and may have implications in terms of improving long-term health because inverted CD4:CD8 ratios are a well-documented risk factor for illness in the HIV-uninfected elderly.
Most intriguing, however, is a trial involving a 12-week analytical treatment interruption (ATI). Data is now available from six individuals who have undergone the ATI and while all experienced a viral load rebound, levels began falling prior to the reinitiation of ART, which June noted was not the case in a prior gene therapy study involving an ATI (an evaluation of a candidate named VRX496). One notable individual controlled viral load to below the level of detection (<50 copies/mL) before ART was restarted. This person turned out to be heterozygous for the delta32 CCR5 deletion, which means that the ZFNs could work more efficiently because only one CCR5 gene in each cell had to be disrupted in order for CCR5 expression to be completely abrogated (instead of two as is normally the case). Importantly, June found a significant correlation between the proportion of modified CD4 T cells and viral load control during the ATI. This suggests that an antiretroviral effect is achievable with the approach, and that the potency of the effect may be boosted if the proportion of modified cells can be increased. In the Q&A period, June was asked if he had assessed whether gene-modified HIV-specific CD4 T cells may have contributed the viral load results; he replied that HIV-specific CD4 T cell responses have not yet been analyzed in the ATI trial.
The last two talks in the final workshop session addressed the development of methods that attempt to specifically target latent HIV and excise it from the DNA of infected cells (or damage the provirus in order to render it non-functional). On paper, at least, these approaches sound very appealing but it was clear that significant hurdles remain. Jan van Lunzen (University Medical Centre Hamburg-Eppendorf) discussed the modification of an enzyme called Cre recombinase to target HIV DNA. The modified version, dubbed Tre recombinase, has successfully excised proviral DNA from cells in vitro and work is now underway to study how it might be delivered. Next steps involve studies in humanized mice using a lentiviral vector to deliver the Tre recombinase to CD34+ stem cells; the vector is designed to be "self-inactivating" in cells that do not contain HIV DNA. As an aside, Jan van Lunzen also mentioned a patient of his who started ART during early infection, was treated for 5 years, then stopped 6 years ago, had a small viral load blip and has been undetectable ever since. HIV RNA cannot be found in blood, gut or CNS. According to van Lunzen, the individual has a "very strong HIV-specific CD4 response," and he highlighted the case as being similar to Christine Rouzioux's report of five individuals treated very early who have controlled viral load to undetectable levels off ART for an average of around five years. These case reports may bode well for prospects for a functional cure, van Lunzen suggested.
Keith Jerome from the Fred Hutchinson Cancer Research Center recounted the efforts of his group to employ different enzymes, endonucleases, to target latent HIV. The idea in this case is to induce mutations in the HIV provirus in order to render it non-functional. Some success has been achieved in vitro but considerable challenges remain in terms of improving the efficiency of targeting and developing delivery methods that might be able to get the endonucleases to where they are needed. Jerome's work is now being supported by a Martin Delaney Collaboratory grant from NIH.
The last word at the 2011 persistence workshop was given to Nobel laureate Françoise Barré-Sinoussi, who outlined the International AIDS Society's development of a Global Scientific Strategy "Towards an HIV Cure" and encouraged audience members to attend an IAS symposium on the subject that will take place in Washington DC immediately ahead of the 2012 International AIDS Conference. Barré-Sinoussi also stressed the importance of the work and the need to continue the momentum which has placed curing HIV infection back at the top of the research agenda.
The 6th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies is scheduled for 2013 in Miami.
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