A new paper from Genoveffa Franchini's group evaluates the impact of transiently depleting CD4 T cells during the priming phase of a DNA/MVA prime-boost vaccine regimen in macaques. After an SIV challenge, significant differences in viral loads were not seen during the acute phase of infection, but began to emerge over time. These increases in viral loads among the CD4-depleted animals were associated with diminished functionality of HIV-specific CD8 T cells compared to the vaccinated macacques that did not undergo CD4 depletion. The authors conclude with the recommendation that "strategies aimed at eliciting effective T-cell responses to HIV by vaccination must broaden their scope beyond generation of antigen-specific CD8+ T-cells to include optimization of the generation of CD4+ T-cells of the right quality and magnitude."
JVI Accepts, published online ahead of print on 30 July 2008
J. Virol. doi:10.1128/JVI.00893-08
Monica Vaccari, Joseph Mattapallil, Kaimei Song, Wen-Po Tsai, Anna Hryniewicz, David Venzon, Maurizio Zanetti, Keith A. Reimann, Mario Roederer, and Genoveffa Franchini
Animal Models & Retroviral Vaccines Section, and Biostatistics & Data Management Section, National Cancer Institute, Bethesda, MD 20892; Department of Microbiology & Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy & Infectious Diseases, Bethesda, MD 20892; Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093; Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
Adaptive CD4+ and CD8+ T-cell responses have been associated with control of HIV/simian immunodeficiency virus (SIV) replication. In here, we have designed a study in macaques to assess more directly the role of CD8 SIV-specific responses in control of viral replication. Indian Rhesus Macaques were immunized with a DNA prime-MVA-SIV boost regimen in normal condition or in condition 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 DNA prime. A group of naïve macaques were also treated with the anti-CD4 depleting antibody as control, and an additional group of macaques immunized in normal condition was depleted of CD8+ T-cells prior challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine induced CD8+ T cells demonstrated that SIV-specific CD8+ T-cells generated in conditions of CD4+ T-cell deficiency expressed low levels of Bcl2 and interleukin-2 (IL-2) and plasma virus level increased over time in these animals. Depletion of CD8+ T-cells prior challenge exposure abrogated vaccine-induced protection as expected. 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 only be afforded 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 post-infection.