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Background. Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)–specific immunity and increase clearance of HIV-1–expressing cells. Methods. We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1–infected adults aged ≥18 to ≤70 years on suppressive antiretroviral therapy with CD4+ counts ≥350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results. Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions. In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1–infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1–specific immunity in a subset of participants. Clinical Trials Registration. NCT02028403.

To the Editor: Van Nood et al. (Jan. 31 issue) 1 found fecal microbiota therapy to be superior to vancomycin for the treatment of recurrent Clostridium difficile infection, but the results of their study should be interpreted with caution. Small, index trials such as this one are vulnerable to exaggerated treatment effects, and subsequent trials typically show decreased effects. 2 Even though the trial was randomized, the results may have been influenced by inequalities among the three treatment groups in terms of either the number of pretreatment recurrences of C. difficile infection or post-treatment exposure to an antimicrobial agent or proton-pump inhibitor . . .

Immunity to a plethora of microbes depends on a diverse repertoire of $na\\ddot{i}ve$ lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of $na\\ddot{i}ve CD4^+$ T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long-lived memory cells.

The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. Here we report an approach to reduce the viral reservoir by activating dormant viral gene expression and directing T lymphocytes to lyse previously latent, HIV-1-infected cells. An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env. This immunomodulatory protein could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. The elimination of latently infected cells is a sought after goal in the treatment of HIV-1 infections. Here the authors develop an approach to eliminate latently HIV-1 infected cells by using an immunomodulatory protein, which can activate viral gene expression in these cells and direct T lymphocytes to lyse them in vitro .

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 + and CD8 + T cells. Co-culturing CD4 + with autologous CD8 + T cells from ART-suppressed HIV + donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 + T cells. This trispecific antibody mediates CD4 + and CD8 + T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection. One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure.

The tracking of antigen-specific T cells in vivo is a useful approach for the study of the adaptive immune response. This protocol describes how populations of T cells specific for a given peptide–major histocompatibility complex (pMHC) epitope can be tracked based solely on T-cell receptor (TCR) specificity as opposed to other indirect methods based on function. The methodology involves the adoptive transfer of TCR transgenic T cells with defined epitope specificity into histocompatible mice and the subsequent detection of these cells through the use of congenic or clonotypic markers. Alternatively, endogenous epitope-specific T cells can be tracked directly through the use of pMHC tetramers. Using magnetic bead-based enrichment and advanced multiparameter flow cytometry, populations as small as five epitope-specific T cells can be detected from the peripheral lymphoid organs of a mouse. The adoptive transfer procedure can be completed within 3 h, whereas analysis of epitope-specific cells from mice can be completed within 6 h.

Immunity to a plethora of microbes depends on a diverse repertoire of naive lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of naive CD4 super(+) T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long- lived memory cells.

Immunity to a plethora of microbes depends on a diverse repertoire of naïve lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of naïve CD4⁺ T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long-lived memory cells.

The two critical hallmarks of adaptive immunity to infectious disease are a diverse antigen receptor repertoire and the memory of which antigen receptors have proven most useful. The CD4+ T cell plays a central role in adaptive immunity to the extent that it provides signals for the function or survival of many other cells in the immune system, including other CD4+ T cells, CD8+ T cells, B cells, and antigen-presenting cells such as macrophage. Although it is known how antigen receptor repertoire diversity is produced, whether mechanisms exist to maintain the survival of a diverse T cell repertoire has not been well addressed by the field. In addition, the conditions required for the generation and maintenance of antigen-specific memory CD4+ T cells are largely unknown. Here, the mechanisms that control the survival and activation of CD4+ T cells are addressed with regard to how diversity might be maintained in the repertoire, and how memory is generated and maintained. To accomplish this, we used adoptive transfer of polyclonal and monoclonal populations of CD4+ T cells into normal host mice, and developed a new highly sensitive method of ex vivo cell detection. Using these tools, we found that low clonal abundance in a polyclonal repertoire favors the survival and activation of naive CD4+ T cells as well as the survival of their memory cell progeny. The inverse relation between survival and clone size demonstrates how the clonal niche both limits and protect a clone's contribution to the T cell repertoire. Furthermore, we found that CD4+ T cell clonal niches are defined by an array of molecular resources such as MHC II, the CD28 ligands, and cytokines for which a cell must compete with other cells for. We also find that resource usage can vary from clone to clone, consistent with the survival and proliferative heterogeneity found using both monoclonal and polyclonal CD4+ T cell populations. Altogether, our results suggest that small CD4+ T cell clone size, enforced through cell competition for molecular resources, simultaneously provides for both the maintenance of antigen receptor repertoire diversity and the ability to produce long-lived memory cells.