Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Memory B-cell depletion is a feature of HIV-2 infection even in the absence of detectable viremia Rita Tendeiro a , Sofia Fernandes a , Russell B. Foxall a , Jose ´ M. Marcelino b,c , Nuno Taveira b,d , Rui S. Soares a , Anto ´ nio P. Baptista a , Rita Cavaleiro a , Perpe ´tua Gomes d,e,f , Rui M.M. Victorino a,g and Ana E. Sousa a Objective: Memory B-cell loss has long been recognized as an important contributor to HIV immunodeficiency. HIV-2 infection, which is characterized by a slow rate of progression to AIDS and reduced to undetectable viremia, provides a unique model to investigate B-cell disturbances. Design and methods: B-cell subsets were evaluated in 38 HIV-2-infected individuals, along with markers of T-cell activation and serum levels of immunoglobulins and a major B-cell homeostatic cytokine, B-cell activating factor (BAFF). Untreated HIV-1- infected and seronegative control individuals were studied in parallel. Statistical analysis was performed using Mann–Whitney tests and Spearman’s correlations. Results: We found that HIV-2 was associated with significant depletion of both unswitched (CD27 þ IgD þ ) and switched (CD27 þ IgD neg ) memory B-cells that directly correlated with T-cell activation, even in individuals with undetectable plasma viral load. Nevertheless, the presence of detectable viremia, even at low levels, was associated with significant memory B-cell loss and higher BAFF levels. Moreover, these alterations were not recovered by antiretroviral-therapy, as treated HIV-2-infected patients showed more pronounced B-cell disturbances, possibly related to their extended length of infection. Conclusion: These first data regarding B-cell imbalances during HIV-2 infection show that, irrespective of viremia, prolonged HIV infection leads to irreversible damage of memory B-cell homeostasis. ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2012, 26:1607–1617 Keywords: AIDS, B-cell activating factor, B-cells, HIV-2, immune activation, memory B-cells Introduction HIV-1 infection is associated with progressive impair- ment of specific humoral responses and loss of memory B-cells that are only partly recovered by antiretroviral therapy (ART) [1–4]. These B-cell disturbances have been linked to the persistent heightened state of immune activation associated with HIV-1 infection [3–5]. In fact, a Unidade de Imunologia Clı ´nica, Instituto de Medicina Molecular, Faculdade de Medicina, b Unidade de Retrovı ´rus e Infecc ¸o ˜es Associadas, Centro de Patoge ´nese Molecular, Faculdade de Farma ´cia, Universidade de Lisboa, c Unidade de Microbiologia Me ´ dica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, d Centro de Investigac ¸a ˜ o Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Cie ˆ ncias da Sau ´ de Egas Moniz, Caparica, e Laborato ´ rio de Biologia Molecular, Servic ¸o de Medicina Transfusional, Centro Hospitalar Lisboa Ocidental, Hospital Egas Moniz, f Centro de Mala ´ria e Doenc ¸as Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, and g Clı ´nica Universita ´ria de Medicina 2, Centro Hospitalar Lisboa Norte, Hospital Universita ´rio de Santa Maria, Lisboa, Portugal. Correspondence to Ana E. Sousa, MD, PhD, Unidade de Imunologia Clı ´nica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal. Tel: +351 21 799 95 25; fax: +351 21 799 95 27; e-mail: asousa@fm.ul.pt Received: 23 February 2012; revised: 23 May 2012; accepted: 1 June 2012. DOI:10.1097/QAD.0b013e3283568849 ISSN 0269-9370 Q 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 1607