CROI 2012: Changing Winds in HIV/AIDS Research
The evolution of HIV/AIDS research is taking place in a faster pace than ever before. Attending this year's conference was an amazing experience and the conference was full of promising endeavors in the search for the cure and biomedical prevention. Humankind has arrived at a tipping point of the HIV/AIDS epidemic and we have the opportunity to get rid of the virus and offer the promise of a generation that's HIV-free.
One symposium -- HIV Latency and Eradication: Clinical Perspectives -- was a main attraction for a large number of researchers, healthcare providers and advocates attending the conference. The topic addressing the "C" word (cure) included the following: mechanisms of viral latency (or how the viral genetic material stays dormant within cells), the identification of compounds that are able to bring out latent virus and force their expression, ways to prevent the dissemination of reactivated HIV and the search for drugs that bring the virus out of its latency state.
As we all know everything began with the serendipitous "Berlin patient" Timothy Brown, who now lives in San Francisco. Five years after receiving bone marrow transplants, Mr. Brown had no sign of HIV infection. A very important factor of these transplants is that they came from a donor with a mutation (CCR5-delta 32) which makes T cells resistant to HIV. However, we still don't know if the eradication of HIV infection in Mr. Brown was provoked by these transplants or other factors.
Several attempts to replicate Mr. Brown's circumstances are now in development at multiple research centers in the world. A small study was presented at CROI 2012 (Abst. 154) with ten subjects diagnosed with AIDS-related lymphoma. They received autologous hematopoietic stem cell transplants and were taking antiretroviral therapy (ART) with plasma viral load <50 copies/mL. After the transplants, viremia persisted (virus in blood stream) in nine out of ten subjects. This study somehow indicates that stem cell transplantation alone does not eradicate HIV, but we need to consider that these ten people did not receive total body irradiation and chemotherapy. It is possible that they carried over HIV from their own transplanted cells.
Another way to replicate the "Berlin patient" is through the use of gene therapy. Sangamo Biosciences Inc. is using zinc finger nuclease technology to produce T-cells resistant to HIV by erasing the CCR5 gene. Data from the first cohorts using modified T-cells were presented at CROI this year (Abst. 155). It is important to note that previous reports of this study have been presented at CROI 2011 and ICAAC 2011.
This report included the results of immunological responders to antiretroviral therapy and immunological non-responders. The difference was based on CD4 counts (>450 cells/mm3 and <500 cells/mm3). All participants received one infusion of CD4 cells modified SB-278. No serious side effects have been reported, only one post-transfusion reaction that resolved after a few days.
After 12 months, CD4 cell increases were observed in these two groups. A very important finding was the normalization of CD4/CD8 T-cell ratios in the majority of subjects. These SB-278 T-cells were also identified in peripheral blood from 90 through 700 days -- a very long time for a transfusion of blood cells. These cells were found in rectal mucosa, which is quite important in the process of immune reconstitution. A subset of participants of these cohorts stopped ART. After an initial increase of viral load, all subjects had significant drops in viral load before reinitiating ART.
On a side note, I'd like to share that I am a participant of this study and that the intervention allowed me to reach a normal ratio of CD4/CD8 (1.11) situation that has been characterized as "functional cure" of the immune system. I did not experience any side effects after the transfusion, and the research team is the most dedicated and professional I have ever worked with since my diagnosis in 1990.
One important step in identifying ways to eradicate HIV is to find compounds that can force viral expression in latent infected resting cells. Several drugs have the potential to activate latent HIV and are currently in study.
A group of Johns Hopkins found a new group of compounds (Abst. 156). The benefits of these new compounds are that they not only induce viral expression in resting latent cells, but do not provoke dangerous global T-cell activation.
One specific compound presented was Vorinistat (Zolinza or SAHA, Abst. 157 LB), which is an HDAC inhibitor and used as an anticancer. Six people who had been stable taking ART with undetectable viral load <50 copies/mL and CD4 cell count >500 cells/mm3 were studied after a single dose of Vorinistat. There was a two-fold increase in histone deacetylation eight hours after the dose. All six participants had intracellular HIV RNA increases, a demonstration that a single dose was able to activate latent virus. The participant did not experience drug-related adverse events or toxicities. There were presentations about similar interventions that seek the activation of "sleeping" HIV RNA using Vorinistat and Disulfiran (Antabuse).
This is an incredible time for research on viral eradication. However, several critical matters should be addressed in the process of this research: the presence of constant funding, validation, and standardization of assays to test HIV latency and reservoirs; and, of course, coordination and collaborative work of researchers and institutions.
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