High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control.

Virus-specific cytotoxic T lymphocytes (CTL) with high levels of functional avidity have been associated with viral clearance in hepatitis C virus infection and with enhanced antiviral protective immunity in animal models. However, the role of functional avidity as a determinant of HIV-specific CTL efficacy remains to be assessed. Here we measured the functional avidities of HIV-specific CTL responses targeting 20 different, optimally defined CTL epitopes restricted by 13 different HLA class I alleles in a cohort comprising 44 HIV controllers and 68 HIV noncontrollers.

Coordinate linkage of HIV evolution reveals regions of immunological vulnerability.

Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted.

Mosaic HIV-1 Gag antigens can be processed and presented to human HIV-specific CD8+ T cells.

Polyvalent mosaic HIV immunogens offer a potential solution for generating vaccines that can elicit immune responses against genetically diverse viruses. However, it is unclear whether key T cell epitopes can be processed and presented from these synthetic Ags and recognized by epitope-specific human T cells. In this study, we tested the ability of mosaic HIV immunogens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors to process and present major HIV clade B and clade C CD8 T cell epitopes in human cells.

Extended high viremics: a substantial fraction of individuals maintain high plasma viral RNA levels after acute HIV-1 subtype C infection.

Objective: The present study addressed two questions: what fraction of individuals maintain a sustained high HIV-1 RNA load after the acute HIV-1C infection peak and how long is a high HIV-1 RNA load maintained after acute HIV-1C infection in this subpopulation?

Design/methods: Plasma HIV-1 RNA dynamics were studied in 77 participants with primary HIV-1C infection from African cohorts in Gaborone, Botswana, and Durban, South Africa. HIV-infected individuals who maintained mean viral load of at least 100,000 (5.0 log(10)) copies/ml after 100 days postseroconversion (p/s) were termed extended high viremics.

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21.

Elite controllers represent a unique group of HIV-1-infected persons with undetectable HIV-1 replication in the absence of antiretroviral therapy. However, the mechanisms contributing to effective viral immune defense in these patients remain unclear. Here, we show that compared with HIV-1 progressors and HIV-1-negative persons, CD4+ T cells from elite controllers are less susceptible to HIV-1 infection.

Epithelial adhesion molecules can inhibit HIV-1-specific CD8⁺ T-cell functions.

Under persistent antigenic stimulation, virus-specific CD8⁺ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.

Factors associated with viral rebound in HIV-1-infected individuals enrolled in a therapeutic HIV-1 gag vaccine trial.

Background: Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression.

Methods: Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis.

Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression.

Recent data suggest that CD8+ T-cell effector activity is an important component in the control of HIV replication in elite controllers (ECs). One critical element of CD8+ T-cell effector function and differentiation is the T-box transcription factor T-bet. In the present study, we assessed T-bet expression, together with the effector proteins perforin, granzyme A (Grz A), granzyme B (Grz B), and granulysin, in HIV-specific CD8+ T cells from ECs (n = 20), chronically infected progressors (CPs; n = 18), and highly active antiretroviral therapy (HAART)-suppressed individuals (n = 19).

Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C.

HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.

Lack of detectable HIV-1-specific CD8(+) T cell responses in Zambian HIV-1-exposed seronegative partners of HIV-1-positive individuals.

Human immunodeficiency virus type 1 (HIV-1)-specific T cell responses were characterized in a blinded study involving infected individuals and their seronegative exposed uninfected (EU) partners from Lusaka, Zambia. HIV-1-specific T cell responses were detected ex vivo in all infected individuals and amplified, on average, 27-fold following in vitro expansion. In contrast, no HIV-1-specific T cell responses were detected in any of the EU partners ex vivo or following in vitro expansion.

Short communication: CD8(+) T cell polyfunctionality profiles in progressive and nonprogressive pediatric HIV type 1 infection.

Pediatric HIV-1 infection is characterized by rapid disease progression and without antiretroviral therapy (ART), more than 50% of infected children die by the age of 2 years. However, a small subset of infected children progresses slowly to disease in the absence of ART. This study aimed to identify functional characteristics of HIV-1-specific T cell responses that distinguish children with rapid and slow disease progression.

Possession of HLA class II DRB1*1303 associates with reduced viral loads in chronic HIV-1 clade C and B infection.

Background: The HLA class II molecules play a central role in the generation of human immunodeficiency virus (HIV)-specific CD4(+) T-helper cells, which are critical for the induction of cytotoxic CD8(+) T cell responses. However, little is known about the impact of HLA class II alleles on HIV disease progression.

Methods: In this study we investigated the effect of HLA class II alleles on HIV disease outcome and HIV-specific T cell responses in a cohort of 426 antiretroviral therapy-naive, HIV-1 clade C-infected, predominantly female black South Africans.

Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers.

Background: Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of human leukocyte antigen (HLA) class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins of elite controllers.

Expression of PD-L1 and PD-L2 on human macrophages is up-regulated by HIV-1 and differentially modulated by IL-10.

PD-1 plays an important role in T cell exhaustion during HIV infection. PD-1 has two ligands: PD-L1, expressed on hematopoietic and nonhematopoietic cells, and PD-L2, limited to DCs and macrophages. Little is known about PD-L1 expression and regulation in human macrophages.

HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function.

Functional defects in cytotoxic CD8(+) T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8(+) T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment.

Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection.

Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-α, IFN-β, myxovirus resistance protein A (MxA), human TRIM5α (huTRIM5α), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants.

Permanent pacing for late-onset atrioventricular block in patients with heart transplantation: a single center experience.

Introduction: The incidence, mechanisms, clinical associations, and outcomes in patients with late-onset (>3 months) atrioventricular (AV) block following heart transplantation are not well known. This study will characterize late-onset AV block following cardiac transplantation.

Methods: We retrospectively reviewed our databases to identify patients who required pacemakers for late-onset AV block postheart and heart-lung transplantation from January 1990 to December 2007.

Impairment of CD1d-restricted natural killer T cells in chronic HIV type 1 clade C infection.

Recent studies suggest that natural killer T (NKT) cells play a role in early antiviral pathogenesis and are rapidly depleted in chronic human immunodeficiency virus type 1 (HIV-1) clade B infection. We aimed to characterize the phenotypic and functional characteristics of NKT cells in HIV-1 clade C-infected Africans at different stages of HIV-1 disease. NKT cell frequencies, subsets, and ex vivo effector functions were assessed using multiparametric flow cytometry in a cross-sectional analysis of cryopreserved peripheral blood mononuclear cells from a cohort of 53 HIV-1 clade C chronically infected South African adults with CD4 T cell counts ranging from 94 to 839 cells/μl.

Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.

CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood.

Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding.

Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes.

Background & Aims: HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus-1, but for HCV the roles of particular alleles and corresponding CD8(+) T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses.

Methods: In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes.

Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.

Background: Despite high potential for HIV-1 genetic variation, the emergence of some mutations is constrained by fitness costs, and may be associated with compensatory amino acid (AA) co-variation. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C.

Methodology/principal Findings: Individuals with CTL responses biased toward Gag presented lower viral loads than individuals with under-represented Gag-specific CTL responses.

Early selection in Gag by protective HLA alleles contributes to reduced HIV-1 replication capacity that may be largely compensated for in chronic infection.

Mutations that allow escape from CD8 T-cell responses are common in HIV-1 and may attenuate pathogenesis by reducing viral fitness. While this has been demonstrated for individual cases, a systematic investigation of the consequence of HLA class I-mediated selection on HIV-1 in vitro replication capacity (RC) has not been undertaken. We examined this question by generating recombinant viruses expressing plasma HIV-1 RNA-derived Gag-Protease sequences from 66 acute/early and 803 chronic untreated subtype B-infected individuals in an NL4-3 background and measuring their RCs using a green fluorescent protein (GFP) reporter CD4 T-cell assay.

HLA-Cw*03-restricted CD8+ T-cell responses targeting the HIV-1 gag major homology region drive virus immune escape and fitness constraints compensated for by intracodon variation.

The potential importance of HLA-C-restricted CD8+ cytotoxic T lymphocytes (CTL) in HIV infection remains undetermined. We studied the dominant HLA-Cw*03-restricted CTL response to YVDRFFKTL(296-304) (YL9), within the conserved major homology region (MHR) of the Gag protein, in 80 HLA-Cw*03-positive individuals with chronic HIV infection to better define the efficacy of the YL9 HLA-C-restricted response. The HLA-Cw*03 allele is strongly associated with HIV sequence changes from Thr-303 to Val, Ile, or Ala at position 8 within the YL9 epitope (P=1.