Reduced protection from simian immunodeficiency virus SIVmac251 infection afforded by memory CD8+ T cells induced by vaccination during CD4+ T-cell deficiency.
Adaptive CD4(+) and CD8(+) T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4(+) T-cell deficiency. Depletion of CD4(+) cells was performed in the immunized macaques at the peak of SIV-specific CD4(+) T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8(+) T cells prior to challenge exposure to SIV(mac251). Analysis of the quality and quantity of vaccine-induced CD8(+) T cells demonstrated that SIV-specific CD8(+) T cells generated under conditions of CD4(+) T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8(+) T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4(+) T cells are critical for the generation of effective CD8(+) T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4(+) and CD8(+) T-cell responses and protect against early depletion of CD4(+) T cells postinfection.
Vaccari
Monica
M
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bldg. 41, Room D804, Bethesda, MD 20892, USA.
Mattapallil
Joseph
J
Song
Kaimei
K
Tsai
Wen-Po
WP
Hryniewicz
Anna
A
Venzon
David
D
Zanetti
Maurizio
M
Reimann
Keith A
KA
Roederer
Mario
M
Franchini
Genoveffa
G
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D049109:Cell Proliferation; D007376:Interleukin-2 / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008214:Lymphocytes / Q000378:metabolism; D008253:Macaca mulatta; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D014611:Vaccination
D007376:Interleukin-2; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D018449:SAIDS Vaccines