Loss of reactivity of vaccine-induced CD4 T cells in immunized monkeys after SIV/HIV challenge Anne-Laure Puaux a , Benoit Delache d , Se ´verine Marconi a , Michel Huerre c , Roger Le Grand d , Yves Rivie `re b and Marie-Louise Michel a Background: Immunization protocols involving priming with DNA and boosting with recombinant live virus vectors such as recombinant modified Vaccinia Ankara (rMVA) are considered as vaccine candidates against HIV. Such protocols improve the outcome of simian/human immunodeficiency virus (SHIV) pathogenic challenge in Rhesus monkeys. Objectives: To investigate the fate of vaccine-induced T cells after a mucosal SHIV challenge. Methods: We immunized Rhesus monkeys (Macaca mulatta) by DNA priming fol- lowed by rMVA boost. After intrarectal challenge with SHIV 89.6P, immunized animals demonstrated early control of viral replication and stable CD4 T-cell counts. We monitored T-cell responses by measuring IFN-g secretion and proliferation. Results: Immunization induced strong and sustained SHIV-specific CD4 and CD8 T-cell responses. CD8 T-cell responses were recalled during acute infection, whereas none of the vaccine-induced SHIV-specific CD4 T-cell responses were recalled. Moreover, most of the CD4 T-cell responses became undetectable in peripheral blood or lymph nodes even after in-vitro peptide stimulation. In contrast, we persistently detected CD4 T-cell responses specific for control recall antigens in infected animals. Conclusion: SHIV 89.6P challenge results in a lack of reactivity of vaccine-induced SHIV-specific CD4 T cells. These results may have important implications in the AIDS vaccine field, especially for the evaluation of new vaccine candidates, both in pre- ventive and therapeutic trials. ß 2005 Lippincott Williams & Wilkins AIDS 2005, 19:757–765 Keywords: CD4 T-cell response, cellular immunity, primate, SHIV, vaccine Abbreviations: AT2, Aldrithiol-2; AZT, Azidothymidine; HBsAg, hepatitis B surface antigen; hybrid DNA, hybrid SHIV/HBsAg particles-expressing DNA; Rh, Rhesus macaque; rMVA, recombinant modified Vaccinia Ankara; SHIV, simian/human immunodeficiency virus; Th, T helper Introduction The evaluation of candidate AIDS vaccines in simian models has proved that vaccine-induced T-cell responses can modulate viral infection [1–4]. Both CD8 and CD4 vaccine-induced T cells appear to be involved in the partial control of infection in primates [5]. Many studies have shown that cytotoxic T lymphocytes (CTL) are involved in the control of HIV and SIV infections. The CTL response is triggered by HIV-specific T helper lymphocytes and by the generation of cytokines, which are produced by activated CD4 T cells. There is evidence From the a INSERM U 370 Carcinogene ` se He ´ patique et Virologie Mole ´ culaire, the b Laboratoire d’Immunopathologie Virale, URA CNRS 1930, De ´partement de Me ´decine Mole ´culaire, the c Unite ´ de Recherche et d’Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris, France, and the d Laboratoire d’Immunopathologie Expe ´rimentale, Service de Neurovirologie, DSV/DRM- CRSSA, Commissariat a ` l’Energie Atomique, Fontenay aux Roses, France. Correspondence to Marie-Louise Michel, INSERM U 370 Carcinogene `se He ´patique et Virologie Mole ´culaire, De ´partement de Me ´decine Mole ´culaire, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel: +33 1 45 68 88 49; fax: +33 1 40 61 38 41; e-mail: maloum@pasteur.fr ISSN 0269-9370 Q 2005 Lippincott Williams & Wilkins 757