Capsules From CROI 2017
March 10, 2017
Ameliorating Immune Reconstitution Inflammatory Syndrome
Immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threatening consequence of the restoration of immune responses to opportunistic pathogens in people who initiate ART at low CD4 T cell counts. Evidence suggests that immune responses can become exaggerated and overly inflammatory as a deficient, dysregulated immune system begins to recover due to ART-mediated HIV suppression. In some cases opportunistic infections can get worse before improving, a problem termed paradoxical IRIS. This is a particularly significant concern in tuberculosis (TB), with a reported mortality rate of around 3%.
In an effort to reduce morbidity and mortality from paradoxical TB-IRIS, Graeme Meintjes and colleagues conducted a randomized trial evaluating a four-week course of the corticosteroid prednisone in individuals at risk. The encouraging results were debuted as a late-breaker at CROI, with Meintjes reporting a significant 30% reduction in the incidence of paradoxical TB-IRIS and a trend toward decreased hospitalizations in the prednisone arm. No evidence of an increase in cancer risk -- which had been raised as a potential issue with prednisone -- was observed. The evidence from the trial suggests that the approach should be adopted as the standard of care for individuals at risk for paradoxical TB-IRIS.
The conference was also cheered by the report of a breakthrough in treating extensively drug-resistant TB, a condition normally requiring the use of debilitating, toxic injectable drugs. A small trial of three oral drugs generated highly promising results, offering hope for progress after decades of stagnation (see Jon Cohen's report in Science).
Encouraging Results With Anti-Inflammatory Antibody
Many studies have reported that HIV infection is associated with an increased risk of arterial inflammation and cardiovascular disease. The pipeline of therapies that might reduce this risk has been discouragingly dry, but at CROI Priscilla Hsue from UCSF presented results from a trial of an anti-inflammatory antibody targeting the cytokine IL-1β that may augur a change for the better. The antibody, canakinumab, is FDA-approved for the treatment of certain autoimmune conditions and is being tested as a therapy for cardiovascular disease in a large (10,000-person) randomized study involving in HIV-negative individuals. Hsue's pilot trial recruited ten HIV-positive people on suppressive ART with a median age of 59. A single dose of canakinumab was administered at baseline and participants followed for eight weeks.
There were significant declines in inflammatory biomarkers: IL-6 levels declined by 30% and high sensitivity c-reactive protein by 41%. Imaging studies revealed a 10% reduction in arterial inflammation. In terms of safety, Hsue noted a transient drop in absolute neutrophil count that resolved by week four and a single case of shingles that did not appear related to any immunological parameters. No significant changes in any biomarkers of HIV disease were seen apart from a 17% drop in CD8 T cell counts between baseline and week two that was not apparent at any other timepoints. CD4 T cell counts, viral load and T cell activation markers were unchanged. Analyses of measures of the HIV reservoir are ongoing.
"We believe this is one of the first immune-based therapies to show a very profound reduction in inflammatory markers in the setting of treated HIV," Hsue said, noting that a larger randomized controlled trial is planned that will give two canakinumab doses and follow 100 participants for 36 weeks.
Dual bNAb Combo Leads to Long-Term SHIV Control
In a symposium on broadly neutralizing antibodies (bNAbs), Michel Nussenzweig premiered unpublished results from a collaborative experiment his laboratory has conducted with Malcolm Martin at the National Institute of Allergy and Infectious Disease (NIAID). The study challenged macaques with a pathogenic SHIV (SHIVAD8) and, starting three days post-infection, administered a combination of two bNAbs, 3BCN117 and 10-1074, thrice weekly for two weeks. Nussenzweig reported that, interestingly, the bNAbs led to prolonged preservation of CD4 T cells and control of viral load in treated animals, with many displaying what he described as an "elite controller phenotype." The depletion of CD8 T cells from some of the macaques led to increased viral load, indicating that the short course of combined bNAbs had positively modulated virus-specific immunity. A paper by Nishimura et al describing the results is now in press at Nature.
Macaque Models in HIV/AIDS Research
Jeff Lifson delivered an exceptional Bernard Fields Memorial Lecture on the role of non-human primate models in HIV/AIDS research. Included in the broad survey were a few nuggets of unpublished data from ongoing work: in a collaboration with Louis Picker, the anti-B cell antibody rituximab has been used to disrupt B cell follicles in elite controller macaques, and this led to reductions in SIV viral load and numbers of T-follicular helper cells in the lymph node, consistent with previous reports that B cell follicles can represent a sanctuary site for the virus. A similar study is now being conducted in SIV-infected macaques treated with ART.
As an alternative approach to the same problem, Lifson cited the work of Dave Ott whose laboratory is investigating the genetic modification of CD8 T cells to express CXCR5, a chemokine receptor that can guide the CD8 T cells into B cell follicles. Lifson showed imaging results demonstrating that this strategy successfully localized CD8 T cells to the follicles, and work is now underway to modify CD8 T cells to express both CXCR5 and T cell receptors targeting SIV antigens.
Cellular and Gene Therapy in Cancer and HIV
Carl June from the University of Pennsylvania gave a plenary talk on the dramatic advances that have occurred in the cancer field involving genetically modified T cells. These approaches typically extract T cells from an individual, genetically modify them in the laboratory to target the desired antigen, then expand and reinfuse the cells, which are described as "chimeric antigen receptor" (CAR) T cells. Impressive results have been obtained against a variety of cancers, although serious safety issues have also emerged in some cases due to the potential for excessively vigorous immune reactions to cause inflammation and pathology. June highlighted that many different clinical trials of this type of approach are currently underway across the globe in cancer, but none are occurring in HIV. June advocated for the development of combination approaches that both engineer HIV resistance in CD4 T cells (such as the Sangamo approach, which June has been involved in studying) and modify CD8 T cell antigen receptors to better target HIV-infected cells for elimination. He also stressed the need to foster engineering innovations to make this type of therapy cheaper, scalable and globally accessible.
Sources of CROI Coverage
High quality reporting from CROI 2017 is available from multiple online sources, including AIDSMap, AVAC, i-Base, HIVandHepatitis.com and NATAP. If you know of other sources I've missed and should include, please leave a comment and I'll update the links.
This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Cure Project.
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