Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. EDITORIAL REVIEW The ‘immunologic advantage’ of HIV-exposed seronegative individuals Masaaki Miyazawa a , Lucia Lopalco b , Francesco Mazzotta c , Sergio Lo Caputo c , Francisco Veas d , Mario Clerici e,f , for the ESN Study Group AIDS 2009, 23:161–175 Keywords: T lymphocytes, immunology, genetics, exposed seronegative Introduction In 1989, a curious phenomenon was described: HIV- specific T-cell responses to the viral envelope and core proteins could be detected in antibody-positive and antigen-negative sexual partners of known HIV-positive men [1]. Two other reports confirmed that initial observation on a total of six exposed seronegative (ESN) individuals, and the author raised the possibility that exposure to HIV that did not result in seroconversion and infection could be associated with the exclusive priming of T lymphocytes [2,3]. Analyses performed in different cohorts of individuals at high risk of HIV infection, including healthcare workers parenterally exposed to HIV and healthy newborns of HIV-infected mothers, revealed that HIV-specific CD4 þ T helper cells, but not antibodies, were present in these persons [4,5]. These observations led to the hypothesis that viral exposure resulting in the exclusive priming of HIV- specific T cells could be associated with protection against the establishment of HIV infection [6]. This hypothesis was greatly strengthened by the inde- pendent observations that although the majority of commercial sex workers in Nairobi (the Pumwani cohort) became HIV-infected within a year, a sizable minority, subsequently estimated to be around 15% of the individuals tested, showed resistance to infection [7]; and that HIV-specific cytotoxic T lymphocytes (CTLs) could be isolated from healthy uninfected newborns of HIV- infected mothers [8]. The novel concept of ‘resistance’ to HIV infection in HIV-exposed individuals was proposed, and the search for immune correlates of such protection against HIV infection was initiated at that point. Subsequent pivotal reports showed that in HIV-exposed but uninfected individuals a particular genetic back- ground, epitomized by the D32 deletion in the CCR5 receptor gene, can be detected [9], the production of soluble factors, including the CD8 þ cell antiviral factor (CAF) and beta-chemokines, is increased [10–12], secretory HIV-specific IgA as well as T helper cells and CTLs can be observed in cervico-vaginal fluids and ejaculates [13,14], and natural killer (NK) cell activity is particularly potent [15]. Thus, 15 years after the first description of the detection of HIV-specific T helper cells in seronegative individuals, the ‘immunologic advantage’ possibly conferring resistance to HIV infection can be a Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan, b Immunobiology of HIV Unit, San Raffaele Scientific Institute, Milan, c Infectious Diseases Unit, S.M. Annunziata Hospital, Firenze, Italy, d Institut de Recherche pour le De ´veloppement and University Montpellier 1, Viral & Molecular Immuno-Physiopathology Lab, Faculty of Pharmacy, Montpellier, France, e Department of Biomedical Sciences and Technologies, University of Milano, and f Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS, Milan, Italy. Correspondence to Mario Clerici, MD, Chair of Immunology, Department of Biomedical Sciences and Technologies, University of Milano, Via F.lli Cervi 93, 20090 Segrate, Milan, Italy. Tel: +39 02 50319679; fax: +39 02 50319677; e-mail: mario.clerici@unimi.it Received: 16 September 2008; accepted: 16 September 2008. DOI:10.1097/QAD.0b013e3283196a80 ISSN 0269-9370 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 161