Impact of long-term antiretroviral therapy interruption and resumption on viral reservoir in HIV-1 infected patients.

: We assessed if the increase on viral reservoir after long-term antiretroviral therapy (ART) interruption (ATI) is reversible upon ART resumption in chronic HIV-1 infected patients. Total HIV-1 DNA increased to pre-ART levels after 48 weeks of ATI to return to pre-ATI levels after 104 weeks of ART resumption. Conversely, integrated HIV-1 DNA remained elevated after ART reinitiation.

New challenges in therapeutic vaccines against HIV infection.

There is a growing interest in developing curative strategies for HIV infection. Therapeutic vaccines are one of the most promising approaches. We will review the current knowledge and the new challenges in this research field.

Cyclosporine A in addition to standard ART during primary HIV-1 infection: pilot randomized clinical trial.

Background: Initiating ART during acute/recent HIV-1 infection reduces viral reservoir formation. It has been proposed that, during this phase, the size of the viral reservoir could be further reduced by the association of immunomodulatory therapy with ART. Contradictory results have emerged, however, from two trials evaluating the impact on immune recovery and the viral reservoir of adding cyclosporine A to ART during primary HIV-1 infection.

Increased expression with differential subcellular location of cytidine deaminase APOBEC3G in human CD4(+) T-cell activation and dendritic cell maturation.

APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T cells are highly permissive for HIV-1 replication, whereas resting CD4(+) T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory.

Adenosine deaminase regulates Treg expression in autologous T cell-dendritic cell cocultures from patients infected with HIV-1.

Regulatory T cells have an important role in immune suppression during HIV-1 infection. As regulatory T cells produce the immunomodulatory molecule adenosine, our aim here was to assess the potential of adenosine removal to revert the suppression of anti-HIV responses exerted by regulatory T cells. The experimental setup consisted of ex vivo cocultures of T and dendritic cells, to which adenosine deaminase, an enzyme that hydrolyzes adenosine, was added.

Structured Treatment Interruptions and Low Doses of IL-2 in Patients with Primary HIV Infection. Inflammatory, Virological and Immunological Outcomes.

Background: Interventions during primary HIV infection (PHI) can modify the clinical course during the chronic phase. The long-term effect of structured treatment interruptions (STI) followed by low doses of interleukin-2 (IL-2) in treated PHI patients is unknown.

Methods: Twelve PHI patients with viral load (VL) <20 copies/mL, CD4 cells >500 cells/mm3, and CD4/CD8 ratio >1, on antiretroviral therapy (ART) initiated within the first 90 days of infection and continued for at least 12 months were included.

HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses.

Unlabelled: HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n = 24) (DC-HIV-1) or nonpulsed DCs (n = 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption.

Loading dendritic cells with PLA-p24 nanoparticles or MVA expressing HIV genes induces HIV-1-specific T cell responses.

Since recent data suggest that nanoparticles and modified vaccinia ankara (MVA) vectors could play a pivotal role in HIV-1 therapeutics and vaccine design, in an ex vivo model of human monocyte-derived dendritic cells (MDDCs), we compared two different loading strategies with HIV-1 vaccine vehicles, either viral or synthetic derived. We used polylactic acid (PLA) colloidal biodegradable particles, coated with HIV Gag antigens (p24), and MVA expressing Gag (rMVA-gag and rMVA-gag/trans membrane) or Tat, Nef and Rev genes (rMVA tat+rev and rMVA nef). PLA-p24 captured by MDDCs from HIV-1 individuals induced a slight degree of MDDC maturation, cytokine and chemokine secretion and migration towards a gradient of CCL19 chemokine and highly increased HIV-specific CD8(+) T-cell proliferation compared with p24 alone.

Effects of different antigenic stimuli on thymic function and interleukin-7/CD127 system in patients with chronic HIV infection.

Background: We tested if an increase in immune activation and a decrease in CD4⁺ T cells induced by different antigenic stimuli could be associated with changes in the thymic function and the interleukin (IL)-7/CD127 system.

Methods: Twenty-six HIV-infected patients under combined antiretroviral therapy (cART) were randomized to receive, during 12 months, a complete immunization schedule (7 vaccines and 15 doses) or placebo. Thereafter, cART was interrupted during 6 months.

Dendritic cell based vaccines for HIV infection: the way ahead.

Dendritic cells have a central role in HIV infection. On one hand, they are essential to induce strong HIV-specific CD4⁺ helper T-cell responses that are crucial to achieve a sustained and effective HIV-specific CD8⁺ cytotoxic T-lymphocyte able to control HIV replication. On the other hand, DCs contribute to virus dissemination and HIV itself could avoid a correct antigen presentation.

A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication.

Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1-infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1-specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to "cART for life." We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV.

Adenosine deaminase enhances the immunogenicity of human dendritic cells from healthy and HIV-infected individuals.

ADA is an enzyme implicated in purine metabolism, and is critical to ensure normal immune function. Its congenital deficit leads to severe combined immunodeficiency (SCID). ADA binding to adenosine receptors on dendritic cell surface enables T-cell costimulation through CD26 crosslinking, which enhances T-cell activation and proliferation.

Influence of episodes of intermittent viremia ("blips") on immune responses and viral load rebound in successfully treated HIV-infected patients.

Presenting episodes of intermittent viremia (EIV) under combination antiretroviral therapy (cART) is frequent, but there exists some controversy about their consequences. They have been described as inducing changes in immune responses potentially associated with a better control of HIV infection. Conversely, it has been suggested that EIV increases the risk of virological failure.

Therapeutic vaccines against HIV infection.

Resistance to medication, adverse effects in the medium-to-long-term and cost all place important limitations on lifelong adherence to combined antiretroviral therapy (cART). In this context, new therapeutic alternatives to 'cART for life' in HIV-infected patients merit investigation. Some data suggest that strong T cell-mediated immunity to HIV can indeed limit virus replication and protect against CD4 depletion and disease progression.

Effects on innate immunity of a therapeutic dendritic cell-based vaccine for HIV-1 infection.

Changes in natural killer (NK) cells according to their phenotype and expression of certain regulatory receptors were analyzed in a double-blind, controlled study of antiretroviral therapy (ART)-untreated HIV-seropositive patients, who had been vaccinated with monocyte-derived dendritic cells pulsed with inactivated HIV-1 autologous virus. This work extends other recently published studies of the same group of HIV-1(+) vaccinated patients, which demonstrated that the viral load significantly decreases and correlates inversely with an increase in HIV-specific T-cell responses in vaccinated patients, but not in controls who received placebo. Our results indicate that this vaccine raises the level of the NK CD56(neg) cell subpopulation, while levels of the NK CD56(dim) and NK CD56(bright) cells expressing the inhibitory receptor CD85j/ILT-2 fell in vaccinated patients.

[Clinical management of acute and chronic human immunodeficiency virus infection before starting antiretroviral treatment].

The evaluation of new cases of HIV infection is relatively common in Spain, where several thousands of patients with new infections are diagnosed each year. Eighty per cent of them have a chronic HIV infection at the first clinical evaluation, which is symptomatic (late presenters) in up to 30% of patients. The initial evaluation of HIV infection is not only directed at determining the clinical, virological (plasma HIV RNA viral load, resistance test and viral tropism) and immunological (CD4+ T-cell cell count) situation of the patients, but must also address the study of their co-infections (hepatitis, tuberculosis) and comorbidities (cardiovascular, hepatic, renal and bone) and the risk of HIV transmission.

An old enzyme for current needs: adenosine deaminase and a dendritic cell vaccine for HIV.

After nearly three decades of searching for a vaccine against HIV, a cure for this pandemic disease still remains elusive. The low immunogenicity of the surface proteins and the huge variability of the virus, together with the immunocompromised status of the host, have made developing an HIV vaccine an uphill battle. Over the past few years, both immunogen design and immunization strategies have improved, providing hope for future, although the anti-HIV responses achieved still remain modest.

Alpha-defensins 1-3 release by dendritic cells is reduced by estrogen.

Background: During pregnancy the immune system of the mother must protect any activation that may negatively affect the fetus. Changes in susceptibility to infection as well as resolution of some autoimmune disorders represent empirical evidence for pregnancy related alterations in immunity. Sex hormones reach extremely high levels during pregnancy and have been shown to have direct effects on many immune functions including the antiviral response of dendritic cells.

Ex vivo production of autologous whole inactivated HIV-1 for clinical use in therapeutic vaccines.

This study provides a detailed description and characterization of the preparation of individualized lots of autologous heat inactivated HIV-1 virions used as immunogen in a clinical trial designed to test an autologous dendritic-cell-based therapeutic HIV-1 vaccine (Clinical Trial DCV-2, NCT00402142). For each participant, ex vivo isolation and expansion of primary virus were performed by co-culturing CD4-enriched PBMCs from the HIV-1-infected patient with PBMC from HIV-seronegative unrelated healthy volunteer donors. The viral supernatants were heat-inactivated and concentrated to obtain 1 mL of autologous immunogen, which was used to load autologous dendritic cells of each patient.

Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8(+) T cell responses in HIV-1-infected individuals.

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes.

Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia.

A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non-myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total-body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA-identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow-up period.

Lymphoid tissue collagen deposition in HIV-infected patients correlates with the imbalance between matrix metalloproteinases and their inhibitors.

We studied the lymphoid tissue biopsies of 20 patients with chronic human immunodeficiency virus (HIV) infection by analyzing collagen deposition, CD4+ cell number, and gene expression of metalloproteinases (MMPs; MMP-2, MMP-9) and tissue inhibitors of MMPs (TIMPs; TIMP-1, TIMP-2). HIV-infected patients had significantly increased collagen deposition (P = .001), fewer CD4+ T cells (P = .

Restoration of T cell responses to toxoplasma gondii after successful combined antiretroviral therapy in patients with AIDS with previous toxoplasmic encephalitis.

Background: It is unknown whether a Toxoplasma gondii-specific T cell response is restored after successful combined antiretroviral therapy (cART) in patients with AIDS and current or previous toxoplasmic encephalitis (TE).

Methods: We performed a multicenter cross-sectional study with 17 healthy T. gondii-positive human immunodeficiency virus (HIV)-1-uninfected individuals and 90 patients coinfected with HIV-1 and T.

A therapeutic dendritic cell-based vaccine for HIV-1 infection.

A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .

Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells.

By interacting with CD26 on the CD4+ T cell surface and with the AdoR A(₂B) on the DC surface, ADA triggers a costimulatory signal for human T cells. The aim of this study was to know whether ADA-mediated costimulation plays a role in the differentiation of T cells. The results show that irrespective of its enzymatic activity and dependent on TNF-α, IFN-γ, and IL-6 action, ADA enhanced the differentiation of CD4+CD45RA+CD45RO⁻ naïve T cells toward CD4+CD25+CD45RO+ Teffs and CD4+CD45RA⁻CD45RO+ memory T cells.