Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody.
OBJECTIVE
To test the efficacy of an immunoconjugate against HIV-1.


METHODS
: A murine monoclonal antibody against the envelope antigen of HIV (P4/D10) was conjugated with the conventional anticancer drug, doxorubicin, and tested against infectious virus and infected cells, both in vitro and in vivo.


METHODS
P4/D10 antibody was incubated with free virus (neutralization) or HIV-infected cells (inhibition) and the resulting infection was measured by a p24 capture enzyme-linked immunosorbent assay. In an HIV-1/MuLV murine challenge model, the ability of the conjugate to inhibit infection in vivo was measured.


RESULTS
Doxorubicin-conjugated P4/D10 neutralized HIV-1IIIB and eliminated intercellular spread and HIV replication in infected Jurkat cells in vitro. The conjugate also protected mice from challenge with HIV-1IIIB/MuLV at an eightfold lower concentration than needed for free antibody, whereas no effects were observed for comparable doses of free drug or irrelevant conjugate controls.


CONCLUSIONS
This indicates that doxorubicin is concentrated to HIV-infected cells by the P4/D10 antibody, significantly (P = 0.0001) contributing to HIV elimination. This concept could also be adapted to eradicate remaining antigen-expressing T cells in patients treated with antiretroviral therapy.
Johansson
Susanne
S
Swedish Institute for Infectious Disease Control, Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 82 Solna, Sweden. susanne.johansson@smi.ki.se
Goldenberg
David M
DM
Griffiths
Gary L
GL
Wahren
Britta
B
Hinkula
Jorma
J
D000704:Analysis of Variance; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D002460:Cell Line; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use*; D015483:HIV Antibodies / Q000008:administration & dosage*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control / Q000628:therapy*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D018796:Immunoconjugates / Q000008:administration & dosage; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009500:Neutralization Tests; D013601:T-Lymphocytes / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects
D000890:Anti-Infective Agents; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D018796:Immunoconjugates; D004317:Doxorubicin