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Key Points• The frequency of CD161 ϩϩ MAIT cells is dramatically decreased in the blood of HIVinfected patients, and they are nonrecoverable with HAART.• Gut sequestration and apoptosis in response to bacterial signals may, amongst others, be mechanisms that contribute to this. IntroductionThe natural course of human immunodeficiency virus type 1 (HIV-1) infection is associated with progressive immune dysfunction, perturbation of immune-cell subsets and increased opportunistic infections. In early disease, there is a dramatic loss of CD4 ϩ T cells from the gastrointestinal tract resulting in impaired mucosal immunity, reduced peripheral CD4 ϩ T-cell count, and increased systemic T-cell activation. [1][2][3][4] These factors contribute to an increased susceptibility to infection with specific organisms such as Mycobacterium tuberculosis and Candida albicans. [5][6][7] In addition, more recent evidence suggests an important role for the loss of CD8 ϩ T cells in susceptibility to bacterial pneumonia and all-cause mortality in HIV infection. 8 MAIT cells are a distinct subset of tissue-infiltrating lymphocytes with antibacterial functions that account for up to one-third of the CD8 ϩ T-cell population in the blood of healthy individuals. [9][10][11] MAIT cells are identified by expression of a semi-invariant T-cell receptor (TCR), iV␣7.2, 10,12,13 which recognizes ligands presented by MHC class I related (MR1) protein. 14 MR1 presentation occurs on dendritic cells, monocytes, and lung epithelial cells in response to bacterial pathogens. 9,10,12 MAIT cells are activated in vitro in an MR1-dependent fashion by a range of bacterial and fungal pathogens, including Escherichia coli, M tuberculosis, and C albicans, 9,10 and in mouse models have been shown to provide protection against bacterial infection. 10,15 In addition, MAIT cells have been shown to be lost from the blood and present in the lungs of patients with active tuberculosis, suggesting they may play an important role in host immunity to M tuberculosis. 9,10 Specific subsets of CD4 ϩ and CD8 ϩ T cells, termed Th17 and Tc17, are defined by their ability to produce IL17A and are important in the regulation of mucosal integrity and antibacterial immunity. [16][17][18][19][20] Early in HIV infection, Th17 cells are lost from the gastrointestinal tract, but may be restored through long-term highly active antiretroviral therapy (HAART) concurrent with a reduction in immune activation levels. 21 The loss of this IL17A and Submitted June 12, 2012; accepted November 26, 2012. Prepublished online as Blood First Edition paper, December 18, 2012; DOI 10.1182 DOI 10. /blood-2012 *C.C. and J.E.U. contributed equally to this work.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 7, 2018. by guest www.bloodjournal.org...

Abstract1 2 6 0 VOLUME 22 | NUMBER 11 | NOVEMBER 2016 nature medicine a r t i c l e s bnAbs have become blueprints for vaccine design owing to their unequalled activity against divergent HIV-1 strains and proven potency in preventing and suppressing HIV-1 infection after in vivo administration [1][2][3][4][5][6][7][8] . Elicitation of potent bnAb activity is relatively rare in natural HIV-1 infection: only 10-25% of infected individuals develop breadth, and an estimated 1% generate highly potent bnAb, or 'elite neutralization' , activity 9,10 . Although much is known about the functional properties of bnAbs, the parameters that govern their evolution in natural infection remain unknown, which is a critical limitation for vaccine development. To date, no vaccine approach has induced bnAb responses that match those elicited in natural infection 1,11 . Defining what restricts and promotes bnAb evolution in certain individuals will be crucial for devising successful vaccine regimens, as the same restrictions are likely to be encountered during immunization.Observations that bnAb activity arises predominantly in viremic individuals after several years of infection and is linked to lower CD4 + cell counts (referred to here as CD4 levels) 4,12-14 strongly suggest that prolonged exposure to viral antigen is needed for induction of bnAbs.Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10 −5 ). Thus, key host, disease and viral determinants, including subtypespecific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.This may be necessary in part to allow the extensive antibody-affinity maturation that is characteristic of many HIV-1-specific bnAbs 15,16 . Similarly, antigen levels may be relevant, as bnAbs have been found to evolve less frequently in individuals with lower viral loads 1,4,13,17 . Individual case studies delineating pathways of bnAb maturation have highlighted the tight interplay between virus escape and antibody adaptation that precedes the development of a broad neutralization response [18][19][20][21][22][23] . In line with this, the viral envelop...