TY - JOUR
T1 - Heroin-HIV-1 (H2) vaccine
T2 - Induction of dual immunologic effects with a heroin hapten-conjugate and an HIV-1 envelope V2 peptide with liposomal lipid A as an adjuvant
AU - Torres, Oscar B.
AU - Matyas, Gary R.
AU - Rao, Mangala
AU - Peachman, Kristina K.
AU - Jalah, Rashmi
AU - Beck, Zoltan
AU - Michael, Nelson L.
AU - Rice, Kenner C.
AU - Jacobson, Arthur E.
AU - Alving, Carl R.
N1 - Funding Information:
We thank Marcus Gallon, Caroline Kittinger, Christopher Spiridon, Courtney Tucker, Sara Levin, Marvin Walker, and Alexander Duval for outstanding technical assistance, and Dr. Amy Elizabeth Beaven (Imaging Core, University of Maryland, College Park) for assistance in confocal microscopy. The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: AE.A244 D11gp120 from Drs. Barton R. Haynes and Hua-Xin Liao,29, 35 and anti-human α4-β7 integrin (Act-1) (cat#11718) from Dr. A.A. Ansari.36 The views expressed in this paper are those of the authors and do not necessarily reflect the official policy of the Department of the Army, Department of Defense, National Institute on Drug Abuse (NIDA), National Institute of Alcohol Abuse and Alcoholism (NIAAA), or the U.S. Government. The work of the Drug Design and Synthesis Section, CBRB, NIDA, and the NIAAA was supported by the NIH Intramural Research Programs of NIDA and NIAAA. This work was supported through a Cooperative Agreement Award (W81XWH-07-2-067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Army Medical Research and Materiel Command. The work was partially supported by an Avant Garde award to GRM from NIDA (NIH grant no. 1DP1DA034787-01).
Funding Information:
1US Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda 20817 MD, USA; 2U.S. Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring 20910 MD, USA; 3Department of Health and Human Services, Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, 9800 Medical Drive, Bethesda 20892 MD, USA and 4National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Drive, Bethesda 20892 MD, USA Correspondence: Carl R. Alving (calving@hivresearch.org)
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - A synthetic heroin analog (MorHap) and a synthetic 42 amino acid V2 loop peptide from A/E strain of HIV-1 gp120 envelope protein that was previously used in a successful phase III vaccine trial were constructed as antigens together with liposomes containing monophosphoryl lipid A as an adjuvant, to explore the feasibility of producing a dual use vaccine both for treatment of heroin addiction and prevention of HIV-1 infection among injection drug users. The V2 peptide was tethered by a palmitoyl fatty acyl tail embedded in the liposomal lipid bilayer, and the heroin analog was conjugated to tetanus toxoid as a carrier protein that was mixed with the adjuvant. Upon comparison of a linear V2 peptide with a cyclic peptide, differences were found in the secondary configurations by circular dichroism, with the tethered cyclic peptide (palm-cyclic peptide) entirely in a random coil, and the tethered linear V2 peptide (palm-linear V2 peptide) entirely in a beta-sheet. Upon immunization of mice, palm-cyclic peptide induced anti-cyclic peptide endpoint titers >106 and was considered to be a better immunogen overall than palm-linear V2 peptide for inducing antibodies to gp120 and gp70-V1V2. The antibodies also inhibited the binding of V2 peptide to the HIV-1 α4β7 integrin receptor. Antibody titers to MorHap, even with the presence of injected cyclic peptide, were very high, and resulted in inhibition of the hyper-locomotion and antinociception effects of injected heroin. From these initial experiments, we conclude that with a potent adjuvant and mostly synthetic constituents, a vaccine directed to heroin and HIV-1 (H2 vaccine) could be a feasible objective.
AB - A synthetic heroin analog (MorHap) and a synthetic 42 amino acid V2 loop peptide from A/E strain of HIV-1 gp120 envelope protein that was previously used in a successful phase III vaccine trial were constructed as antigens together with liposomes containing monophosphoryl lipid A as an adjuvant, to explore the feasibility of producing a dual use vaccine both for treatment of heroin addiction and prevention of HIV-1 infection among injection drug users. The V2 peptide was tethered by a palmitoyl fatty acyl tail embedded in the liposomal lipid bilayer, and the heroin analog was conjugated to tetanus toxoid as a carrier protein that was mixed with the adjuvant. Upon comparison of a linear V2 peptide with a cyclic peptide, differences were found in the secondary configurations by circular dichroism, with the tethered cyclic peptide (palm-cyclic peptide) entirely in a random coil, and the tethered linear V2 peptide (palm-linear V2 peptide) entirely in a beta-sheet. Upon immunization of mice, palm-cyclic peptide induced anti-cyclic peptide endpoint titers >106 and was considered to be a better immunogen overall than palm-linear V2 peptide for inducing antibodies to gp120 and gp70-V1V2. The antibodies also inhibited the binding of V2 peptide to the HIV-1 α4β7 integrin receptor. Antibody titers to MorHap, even with the presence of injected cyclic peptide, were very high, and resulted in inhibition of the hyper-locomotion and antinociception effects of injected heroin. From these initial experiments, we conclude that with a potent adjuvant and mostly synthetic constituents, a vaccine directed to heroin and HIV-1 (H2 vaccine) could be a feasible objective.
UR - http://www.scopus.com/inward/record.url?scp=85021678697&partnerID=8YFLogxK
U2 - 10.1038/s41541-017-0013-9
DO - 10.1038/s41541-017-0013-9
M3 - Article
AN - SCOPUS:85021678697
SN - 2059-0105
VL - 2
JO - npj Vaccines
JF - npj Vaccines
IS - 1
M1 - 13
ER -