Caecum OX40+CD4 T-cell subset associates with mucosal damage and key markers of disease in treated HIV-infection.

Background: Blood OX40-expressing CD4 T-cells from antiretroviral (ART)-treated people living with HIV (PWH) were found to be enriched for clonally-expanded HIV sequences, hence contributing to the HIV reservoir. OX40-OX40L is also a checkpoint regulator of inflammation in multiple diseases. We explored gut mucosal OX40+CD4+ T-cells and their potential significance in HIV disease.

CCR5 Δ32 homozygous cord blood allogeneic transplantation in a patient with HIV: a case report.

Background: Allogeneic donor CCR5 Δ32 homozygous haemopoietic cell transplantation (HCT) provides the only evidence to date of long-term control of HIV infection. However, availability of conventional CCR5 Δ32 homozygous donors is insufficient to develop this as a therapeutic strategy further.

Methods: We present a 37-year-old patient with HIV-1 infection and aggressive lymphoma who had disease progression after five lines of radiochemotherapy including an autologous HCT, and in the absence of matched sibling donors, received an allogeneic HCT with four of six HLA-matched CCR5 Δ32 homozygous cord blood cells (StemCyte, Covina, CA), supported with purified CD34+ cells from a haploidentical sibling.

Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very Early Antiretroviral Therapy.

Background: Combination antiretroviral therapy (cART) generally suppresses the replication of the human immunodeficiency virus type 1 (HIV-1) but does not cure the infection, because proviruses persist in stable latent reservoirs. It has been proposed that low-level proviral reservoirs might predict longer virologic control after discontinuation of treatment. Our objective was to evaluate the impact of very early initiation of cART and temporary treatment interruption on the size of the latent HIV-1 reservoir in vertically infected children.

A non-infectious cell-based phenotypic assay for the assessment of HIV-1 susceptibility to protease inhibitors.

Objectives: HIV-1 genotyping is widely accepted as a diagnostic tool to optimize therapy changes in patients whose antiretroviral regimen is failing. Phenotyping can substantially complement the information obtained from genotyping, especially in the presence of complex mutational patterns. However, drug susceptibility tests are laborious and require biosafety facilities.

A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy.

Background: The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain.

Methods: The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses.

Exosomes and retroviruses: the chicken or the egg?

Retroviruses appropriate pre-existing cellular machineries to propagate. In the last decade, impressive similarities have been observed in the generation and dissemination in the host cells of retroviruses and small cellular vesicles known as exosomes. These cellular vesicles are thought to facilitate intercellular communication processes and mediate immune functions.

HIV and mature dendritic cells: Trojan exosomes riding the Trojan horse?

Exosomes are secreted cellular vesicles that can induce specific CD4(+) T cell responses in vivo when they interact with competent antigen-presenting cells like mature dendritic cells (mDCs). The Trojan exosome hypothesis proposes that retroviruses can take advantage of the cell-encoded intercellular vesicle traffic and exosome exchange pathway, moving between cells in the absence of fusion events in search of adequate target cells. Here, we discuss recent data supporting this hypothesis, which further explains how DCs can capture and internalize retroviruses like HIV-1 in the absence of fusion events, leading to the productive infection of interacting CD4(+) T cells and contributing to viral spread through a mechanism known as trans-infection.

Idd9.1 locus controls the suppressive activity of FoxP3+CD4+CD25+ regulatory T-cells.

Objective: The approximately 45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.

The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates.

Objective: : Resistance to raltegravir is associated with three genetic pathways defined by the mutations Y143R/C, Q148H/R/K or N155H in integrase, which also infer a viral fitness cost. Additionally, the three major HIV-1 drug-targeted enzymes protease, reverse transcriptase and integrase mature from the same polyprotein, suggesting the potential for interaction between them. This study aims to elucidate the relative contribution of protease-reverse transcriptase, integrase and the rest of the HIV-1 genome to viral fitness and susceptibility to raltegravir.

Effect of the human immunodeficiency virus type 1 reverse transcriptase polymorphism Leu-214 on replication capacity and drug susceptibility.

A negative association between polymorphism Leu-214 and type-1 thymidine analogue mutations (TAM1) and a positive association with a clinically favorable virological response to thymidine analogue-based combination antiretroviral therapy have been described. In this study, the impact of Leu-214 on replication capacity and resistance to zidovudine (ZDV) of viruses containing TAM1 or TAM2 was determined. Leu-214 decreased the growth rate of viruses bearing Tyr-215, as well as their resistance to ZDV.

Contribution of immunological and virological factors to extremely severe primary HIV type 1 infection.

Background: During acute human immunodeficiency virus (HIV) infection, high viral loads and the induction of host immune responses typically coincide with the onset of clinical symptoms. However, clinically severe presentations during acute HIV type 1 (HIV-1) infection, including AIDS-defining symptoms, are unusual.

Methods: Virus isolates were tested for clade, drug susceptibility, coreceptor use, and growth rate in 2 case reports of sexual transmission of HIV-1 infection.

Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway.

Exosomes are secreted cellular vesicles that can be internalized by dendritic cells (DCs), contributing to antigen-specific naive CD4(+) T-cell activation. Here, we demonstrate that human immunodeficiency virus type 1 (HIV-1) can exploit this exosome antigen-dissemination pathway intrinsic to mature DCs (mDCs) for mediating trans-infection of T lymphocytes. Capture of HIV-1, HIV-1 Gag-enhanced green fluorescent protein (eGFP) viral-like particles (VLPs), and exosomes by DCs was up-regulated upon maturation, resulting in localization within a CD81(+) compartment.

Functional consequences of human immunodeficiency virus escape from an HLA-B*13-restricted CD8+ T-cell epitope in p1 Gag protein.

The observed association between HLA-B*13 and control of human immunodeficiency virus type 1 (HIV-1) infection has been linked to the number of Gag-specific HLA-B*13-restricted cytotoxic T-cell (CTL) responses identified. To date, the Gag escape mutations described that result in an in vitro fitness cost to the virus have been located within structural protein p24 only. Here we investigated the hypothesis that CTL escape mutations within other regions of HIV Gag may also reduce viral fitness and contribute to immune control.

Anti-peripherin B lymphocytes are positively selected during diabetogenesis.

Rearrangement analysis of immunoglobulin genes is an exceptional opportunity to look back at the B lymphocyte differentiation during ontogeny and the subsequent immune response, and thus to study the selective pressures involved in autoimmune disorders. In a recent study to characterize the antigenic specificity of B lymphocytes during T1D progression, we generated hybridomas of islet-infiltrating B lymphocytes from NOD mice and other related strains developing insulitis, but with different degrees of susceptibility to T1D. We found that a sizable proportion of hybridomas produced monoclonal antibodies reactive to peripherin, an intermediate filament protein mainly found in the peripheral nervous system.

Peripherin is a relevant neuroendocrine autoantigen recognized by islet-infiltrating B lymphocytes.

Most of our knowledge of the antigenic repertoire of autoreactive B lymphocytes in type 1 diabetes (T1D) comes from studies on the antigenic specificity of both circulating islet-reactive autoantibodies and peripheral B lymphocyte hybridomas generated from human blood or rodent spleen. In a recent study, we generated hybridoma cell lines of infiltrating B lymphocytes from different mouse strains developing insulitis, but with different degrees of susceptibility to T1D, to characterize the antigenic specificity of islet-infiltrating B lymphocytes during progression of the disease. We found that many hybridomas produced mAbs restricted to the peripheral nervous system (PNS), thus indicating an active B lymphocyte response against PNS elements in the pancreatic islet during disease development.

Phenotype and functional characteristics of islet-infiltrating B-cells suggest the existence of immune regulatory mechanisms in islet milieu.

B-cells participate in the autoimmune response that precedes the onset of type 1 diabetes, but how these cells contribute to disease progression is unclear. In this study, we analyzed the phenotype and functional characteristics of islet-infiltrating B-cells in the diabetes-prone NOD mouse and in the insulitis-prone but diabetes-resistant (NOD x NOR)F1 mouse. The results indicate that B-cells accumulate in the islets of both mice influenced by sex traits.

Relative fitness and replication capacity of a multinucleoside analogue-resistant clinical human immunodeficiency virus type 1 isolate with a deletion of codon 69 in the reverse transcriptase coding region.

Deletions, insertions, and amino acid substitutions in the beta3-beta4 hairpin loop-coding region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been associated with resistance to nucleoside RT inhibitors when appearing in combination with other mutations in the RT-coding region. In this work, we have measured the in vivo fitness of HIV-1 variants containing a deletion of 3 nucleotides affecting codon 69 (Delta69) of the viral RT as well as the replication capacity (RC) ex vivo of a series of recombinant HIV-1 variants carrying an RT bearing the Delta69 deletion or the T69A mutation in a multidrug-resistant (MDR) sequence background, including the Q151M complex and substitutions M184V, K103N, Y181C, and G190A. Patient-derived viral clones having RTs with Delta69 together with S163I showed increased RCs under drug pressure.

Islet-infiltrating B-cells in nonobese diabetic mice predominantly target nervous system elements.

B-cells accumulate in pancreatic islets during the autoimmune response that precedes the onset of type 1 diabetes. However, the role and antigenic specificity of these cells remain a mystery. To elucidate the antigenic repertoire of islet-infiltrating B-cells in type 1 diabetes, we generated hybridoma cell lines of islet-infiltrating B-cells from nonobese diabetic (NOD) mice and NOD mice expressing a diabetogenic T-cell receptor (8.