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Effects of Immunization with CCR5-Based Cycloimmunogen on Simian/HIV_SF162P3 Challenge¹

Shogo Misumi^2,*, Daisuke Nakayama^2,*, Masashi Kusaba^*, Takaaki Iiboshi^*, Ryouzaburo Mukai, Kuniomi Tachibana, Tadashi Nakasone, Mamoru Umeda, Hideaki Shibata, Masafumi Endo^*, Nobutoki Takamune^* and Shozo Shoji^3,*

^* Department of Pharmaceutical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Tsukuba Primate Center for Medical Science, National Institute of Infectious Diseases, Tsukuba, Ibaraki, Japan; Research Laboratory, Nissui Pharmaceutical, Ibaraki, Japan; and AIDS Research Center, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan

A synthetic cycloimmunogen targeting the HIV-1 coreceptor CCR5 was evaluated for its capacity to induce CCR5-specific Abs with anti-HIV-1 activity in cynomolgus macaques. The cyclic closed-chain dodecapeptide (cDDR5) mimicking the conformation-specific domain of human CCR5 was chemically prepared, in which the Gly-Glu dipeptide links the amino and carboxy termini of the decapeptidyl linear chain (Arg¹⁶⁸ to Thr¹⁷⁷) derived from the undecapeptidyl arch (Arg¹⁶⁸ to Cys¹⁷⁸) of extracellular loop-2 in CCR5. The immunization of cynomolgus macaques with the cDDR5-conjugated multiple-Ag peptide (cDDR5-MAP) induced anti-cDDR5 serum production for 15 wk after the third immunization. The antisera raised against cDDR5-MAP reacted with both human and macaque CCR5s, and potently suppressed infection by the R5 HIV-1 laboratory isolate (HIV_JRFL), R5 HIV-1 primary isolates (clade A:HIV_93RW004 and clade C:HIV_MJ4), and a pathogenic simian/HIV (SHIV_SF162P3) bulk isolate in vitro. To examine the prophylactic efficacy of anti-CCR5 serum Ab for acute HIV-1 infection, cynomolgus macaques were challenged with SHIV_SF162P3. The cDDR5-MAP immunization attenuated the acute phase of SHIV_SF162P3 replication. The geometric mean plasma viral load in the vaccinated macaques was 217.10 times lower than that of the control macaques at 1 wk postchallenge. Taken together, these results suggest that cDDR5-MAP immunization is an effective prophylactic vaccine strategy that suppresses and delays viral propagation during the initial HIV-1 transmission for the containment of HIV-1 replication subsequent to infection.

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