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1.
Science ; 382(6676): 1270-1276, 2023 12 15.
Article in English | MEDLINE | ID: mdl-38096385

ABSTRACT

Current HIV vaccines designed to stimulate CD8+ T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8+ T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8+ T cell response may require a vaccination strategy that drives further TCR clonal selection.


Subject(s)
AIDS Vaccines , Cell Degranulation , Cytotoxicity, Immunologic , HIV Infections , T-Lymphocytes, Cytotoxic , Humans , AIDS Vaccines/immunology , Clone Cells , HIV Infections/prevention & control , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Cytotoxic/immunology , Cell Degranulation/immunology
2.
J Hosp Med ; 16(4): 219-222, 2021 04.
Article in English | MEDLINE | ID: mdl-33734980

ABSTRACT

A patient's supine posture redistributes plasma into the vascular space, leading to dilution of blood constituents. The extent to which posture may influence identification of hospital-acquired anemia is unknown. Patients in this quasi-experimental study had blood obtained for hemoglobin measurement while recumbent for at least 6 hours, and then again after sitting upright for at least 1 hour. Of the 35 patients who completed the study, 13 were women (37%). Patients had a median increase in hemoglobin of 0.60 g/dL (range, -0.6 to 1.4 g/dL) with sitting, a 5.2% (range, (-4.5% to 15.1%) relative change (P < .001). Ten of 35 patients (29%) exhibited an increase in hemoglobin of 1.0 g/dL or more. Posture influences hemoglobin levels in hospitalized patients on general medicine wards; this knowledge may help curb unnecessary testing to evaluate small changes in hemoglobin concentration.


Subject(s)
Anemia , Supine Position , Anemia/diagnosis , Female , Hemoglobins , Humans , Male , Time Factors
3.
PLoS One ; 14(12): e0225806, 2019.
Article in English | MEDLINE | ID: mdl-31830058

ABSTRACT

Plasmacytoid dendritic cells (PDCs) and their production of interferon-alpha (IFN-α) are believed to play an important role in human immunodeficiency virus, type I (HIV-1) pathogenesis. PDCs produce IFN-α and other proinflammatory cytokines through stimulation of Toll-like receptor 7 (TLR7) and TLR9 present in endosomal compartments. TLR7 recognizes single-stranded viral RNA, while TLR9 recognizes unmethylated DNA. In this study, we examined the mechanisms that may underlie variations in IFN-α production in response to HIV, and the impact of these variations on HIV pathogenesis. In four distinct cohorts, we examined PDC production of IFN-α upon stimulation with inactivated HIV-1 particles and unmethylated DNA. The signaling cascade of TLR7 bifurcates at the myeloid differentiation protein 88 (MyD88) adaptor protein to induce expression of either IFN-α or TNF-α. To determine whether variations in IFN-α production are modulated at the level of the receptor complex or downstream of it, we correlated production of IFN-α and TNF-α following stimulation of TLR7 or TLR9 receptors. Flow cytometry detection of intracellular cytokines showed strong, direct correlations between IFN-α and TNF-α expression in all four cohorts, suggesting that variations in IFN-α production are not due to variations downstream of the receptor complex. We then investigated the events upstream of TLR binding by using lipid-like vesicles to deliver TLR ligands directly to the TLR receptors, bypassing the need for CD4 binding and endocytosis. Similar tight correlations were found in IFN-α and TNF-α production in response to the TLR ligands. Taken together, these results strongly suggest that differences in IFN-α production depend on the regulatory processes at the level of the TLR7 receptor complex. Additionally, we found no association between IFN-α production before HIV infection and disease progression.


Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Dendritic Cells/metabolism , Dendritic Cells/virology , HIV-1/physiology , Interferon-alpha/biosynthesis , Toll-Like Receptor 7/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Cohort Studies , Dendritic Cells/drug effects , Disease Progression , Fatty Acids, Monounsaturated/pharmacology , Female , HIV Infections/metabolism , HIV Infections/virology , Humans , Interferon-alpha/metabolism , Male , Myeloid Differentiation Factor 88/metabolism , Quaternary Ammonium Compounds/pharmacology , Signal Transduction/drug effects , Toll-Like Receptor 7/antagonists & inhibitors , Toll-Like Receptor 9/antagonists & inhibitors , Toll-Like Receptor 9/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Viral Load/drug effects
4.
EBioMedicine ; 2(1): 46-58, 2015 Jan.
Article in English | MEDLINE | ID: mdl-26137533

ABSTRACT

Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8(+) T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8(+) T-cell specificity and function of B*27/57(neg) LTNP/EC (n = 23), B*27/57(pos) LTNP/EC (n = 23) and B*27/57(neg) progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57(neg) LTNP/EC did not target more highly conserved epitopes, their CD8(+) T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57(pos) LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8(+) T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytotoxicity, Immunologic , HIV-1/immunology , HLA Antigens/immunology , Immunodominant Epitopes/immunology , Amino Acid Sequence , Entropy , HIV Infections/immunology , HIV Infections/virology , Humans , Immunodominant Epitopes/chemistry , Molecular Sequence Data , gag Gene Products, Human Immunodeficiency Virus/immunology
5.
PLoS One ; 8(8): e71879, 2013.
Article in English | MEDLINE | ID: mdl-23951263

ABSTRACT

Resting CD4+T cells infected with HIV persist in the presence of suppressive anti-viral therapy (ART) and are barriers to a cure. One potential curative approach, therapeutic vaccination, is fueled by recognition of the ability of a subset of elite controllers (EC) to control virus without therapy due to robust anti-HIV immune responses. Controllers have low levels of integrated HIV DNA and low levels of replication competent virus, suggesting a small reservoir. As our recent data indicates some reservoir cells can produce HIV proteins (termed GPR cells for Gag-positive reservoir cells), we hypothesized that a fraction of HIV-expressing resting CD4+T cells could be efficiently targeted and cleared in individuals who control HIV via anti-HIV cytotoxic T lymphocytes (CTL). To test this we examined if superinfected resting CD4+T cells from EC express HIV Gag without producing infectious virus and the susceptibility of these cells to CTL. We found that resting CD4+T cells expressed HIV Gag and were cleared by autologous CD8+T cells from EC. Importantly, we found the extent of CTL clearance in our in vitro assay correlates with in vivo reservoir size and that a population of Gag expressing resting CD4+T cells exists in vivo in patients well controlled on therapy.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV-1/immunology , T-Lymphocytes, Cytotoxic/immunology , gag Gene Products, Human Immunodeficiency Virus/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cells, Cultured , Coculture Techniques , DNA, Viral/genetics , HIV Infections/immunology , HIV Infections/virology , HIV-1/genetics , HIV-1/metabolism , Humans , Real-Time Polymerase Chain Reaction , T-Lymphocytes, Cytotoxic/virology , gag Gene Products, Human Immunodeficiency Virus/genetics , gag Gene Products, Human Immunodeficiency Virus/metabolism
6.
PLoS Pathog ; 9(2): e1003195, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23468632

ABSTRACT

Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8(+) T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4(+) T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4(+) T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0-91.7%] vs. 23.7% [0.0-58.0%], p = 0.002). In addition, significant correlations between ICE and viral load (r = -0.57, p = 0.01), and between granzyme B delivery and ICE (r = 0.89, p<0.001) were observed. Furthermore, the CD8(+) T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (p = 0.004). These findings support that greater lytic granule loading of virus-specific CD8(+) T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated.


Subject(s)
CD8-Positive T-Lymphocytes/pathology , Immunity , Macaca mulatta/virology , Simian Acquired Immunodeficiency Syndrome/pathology , T-Lymphocytes, Cytotoxic/pathology , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Disease Progression , Host-Pathogen Interactions , Macaca mulatta/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology , Virus Replication
7.
Blood ; 119(20): 4645-55, 2012 May 17.
Article in English | MEDLINE | ID: mdl-22490332

ABSTRACT

True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8(+) T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8(+) T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.


Subject(s)
HIV Infections/immunology , HIV Long-Term Survivors , HIV-1/immunology , Adult , Female , HIV Infections/blood , HIV Infections/virology , HIV Seropositivity/immunology , HIV Seropositivity/virology , HIV-1/physiology , Humans , Male , Middle Aged , Viral Load , Virus Replication/immunology , Virus Replication/physiology
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