February 19, 2015
A paper published yesterday in Nature has stirred considerable excitement and widespread media coverage. Led by the laboratory of Michael Farzan at The Scripps Research Institute, the research involves a newly designed inhibitor of HIV named eCD4-Ig. The inhibitor is designed to bind the HIV envelope at sites that attach to CD4 and CCR5 molecules on CD4 T cells; blocking this interaction prevents HIV from gaining entry and infecting the cell. In laboratory experiments, eCD4-Ig showed activity against an unprecedentedly broad array of HIV and SIV variants, including viruses known to be resistant to even potent neutralizing antibodies. In addition to the greater breadth, activity was generally achieved at lower concentrations than has been documented with the broadly neutralizing antibodies (bNAbs) described to date. Due to similarities between HIV envelope binding to CCR5 and CXCR4 co-receptors, eCD4-Ig also proved capable of neutralizing CXCR4-dependent virus isolates. These results prompted the researchers to explore the preventive potential of eCD4-Ig in the rhesus macaque model, and it is the outcome of this part of the study that has particularly spurred the publicity.
To deliver the eCD4-Ig (which was modified to match the rhesus macaque form of the protein), the researchers chose to incorporate the gene encoding eCD4-Ig into an AAV vector. AAV vectors are taken up by muscle tissue and act as a factory for producing the encoded protein; for this reason they have been widely used in gene therapy studies (to deliver factor IX to hemophiliacs, for example) and are also under evaluation as a method to deliver neutralizing antibodies against HIV. One small twist with the eCD4-Ig macaque study is that the researchers delivered an 80/20 mix of two AAV vectors: one encoding eCD4-Ig, the other encoding the gene for tyrosylprotein sulfotransferase 2 (TPST2). The role of the TPST2 is to alter the eCD4-Ig protein via a process called sulfation, and this is necessary to make the eCD4-Ig active. It's not evident from the paper whether preliminary experiments indicated the addition of TPST2 was needed, or if the decision was based solely on biological considerations.
Four macaques were administered the AAV vector mix and four served as controls. All animals were subsequently challenged intravenously with escalating doses of a hybrid SIV/HIV virus (SHIV-AD8). The four controls all eventually became infected, but the AAV recipients resisted infection despite multiple challenges over a 34-week period. Serum levels of eCD4-Ig were stable at the end of the 40-week study, and sera from the macaques neutralized HIV in vitro just as effectively as eCD4-Ig produced in the laboratory. Although antibody responses against the eCD4-Ig could be detected in the macaques, the levels were very low (much lower than were seen against the broadly neutralizing monoclonal antibodies 3BNC117, NIH45-45, 10-1074 and PGT121).
The researchers cite several features of the approach that may make it suitable for advancing into human trials.
But there are also some potential hurdles and caveats:
The paper does not explicitly discuss whether eCD4-Ig might have therapeutic potential (focusing instead on prevention) but notes that it is a potent inducer of antibody-dependent cell-mediated cytotoxicity (ADCC); it has been postulated that induction of ADCC against HIV-infected cells could be a component of a combination strategy to eliminate HIV reservoirs. A press release from the National Institute of Allergy and Infectious Diseases (NIAID) addresses the issue more directly and refers to eCD4-Ig as a "potential long-acting HIV therapeutic," with a quote from Michael Farzan stating: "if one could inject either eCD4-Ig or our gene therapy tool into people with HIV infection, it might control HIV for extended periods in the absence of antiretroviral drugs." The release also notes that therapeutic studies in macaques are getting underway, funded under NIAID's recent Beyond HAART: Innovative Therapies to Control HIV-1 RFA.
According to an article in the New York Times, the researchers are considering a stepwise development plan that would first test infusions of the eCD4-Ig protein in healthy volunteers, then evaluate AAV-delivered eCD4-Ig (and, presumably, TPST2) in HIV-positive individuals, then finally move the AAV-delivered version into trials in HIV-negative populations at high risk of HIV infection. In the Wall Street Journal, Farzan articulates the hope that "human trials could begin within a year" but this may be overly optimistic; given the additional work that needs to be done, two or three years might be more realistic.
Links to several news articles about the research are below.
Stopping HIV with an artificial protein -- Jon Cohen, Science Magazine, February 18, 2015
New Approach to Blocking H.I.V. Raises Hopes for an AIDS Vaccine -- Donald G. McNeil Jr., New York Times, February 18, 2015
Molecule Shows Ability to Block AIDS Virus -- Betsy McKay, Wall Street Journal, Feb. 18, 2015
Update 3/6/15: A webcast of Michael Farzan's presentation at CROI 2015 is now available. In the talk Farzan reveals that, since the publication of the Nature paper, the eCD4-Ig recipients have been challenged with two higher doses of SHIV-AD8 and remain uninfected.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.
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