Sequential immunization of macaques with two differentially attenuated vaccines induced long-term virus-specific immune responses and conferred protection against AIDS caused by heterologous simian human immunodeficiency Virus (SHIV(89.6)P).
Four rhesus macaques were sequentially immunized with live vaccines DeltavpuDeltanefSHIV-4 (vaccine-I) and Deltavpu SHIV(PPC) (vaccine-II). The vaccine viruses did not replicate productively in the peripheral blood mononuclear cells (PBMCs) of the vaccinated animals. All four animals developed binding antibodies against both the vaccine-I and -II envelope glycoproteins but neutralizing antibodies only against vaccine-I. They developed vaccine virus-specific CTLs that also recognized homologous as well as heterologous pathogenic SHIVs. Thirty weeks after the last immunization, the vaccinated animals and three unvaccinated control animals were challenged iv with a highly virulent heterologous SHIV(89.6)P. As expected, the three unvaccinated control animals developed large numbers of infectious PBMCs, high plasma viremia, and precipitous loss of CD4(+) T cells. Two controls did not develop any immune response and succumbed to AIDS in about 6 months. The third control animal developed neutralizing antibodies and had a more chronic disease course, but eventually succumbed to AIDS-related complications 81 weeks after inoculation. The four vaccinated animals became infected with challenge virus as indicated by the presence of challenge virus-specific DNA in the PBMCs and RNA in plasma. However, virus in these animals replicated approximately 200- to 60,000-fold less efficiently than in control animals and eventually, plasma viral RNA became undetectable in three of the four vaccinates. The animals maintained normal CD4(+) T-cell levels throughout the observation period of 85 weeks after a transient drop at Week 3 postchallenge. They also maintained CTL responses throughout the observation period. These studies thus showed that the graded immunization schedule resulted in a safe and highly effective long-lasting immune response that was associated with protection against AIDS by highly pathogenic heterologous SHIV(89.6)P.
Kumar
A
A
Laboratory of Viral Pathogenesis, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA. akumar@kumc.edu
Lifson
J D
JD
Li
Z
Z
Jia
F
F
Mukherjee
S
S
Adany
I
I
Liu
Z
Z
Piatak
M
M
Sheffer
D
D
McClure
H M
HM
Narayan
O
O
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D003602:Cytotoxicity, Immunologic; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D006678:HIV / Q000276:immunology* / Q000302:isolation & purification; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D007114:Immunization; D007115:Immunization Schedule; D008198:Lymph Nodes / Q000821:virology; D008253:Macaca mulatta; D009500:Neutralization Tests; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000302:isolation & purification; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D019562:Viral Load
D016915:AIDS Vaccines; D000914:Antibodies, Viral; D004279:DNA, Viral; D015483:HIV Antibodies; D012367:RNA, Viral; D014613:Vaccines, Attenuated