scholarly journals Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection

2021 ◽  
Vol 17 (12) ◽  
pp. e1010105
Author(s):  
Vishakha Sharma ◽  
Matthew Creegan ◽  
Andrey Tokarev ◽  
Denise Hsu ◽  
Bonnie M. Slike ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebrospinal Fluid ◽  
T Cell ◽  
Viral Rna ◽  
Cd4 T Cell ◽  
Cell Infection ◽  
Viral Reservoirs ◽  
Acute Hiv ◽  
Shiv Infection ◽  
Hiv 1

HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus. We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6; Fiebig III/IV). Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies.

scholarly journals Virion encapsidated HIV-1 Vpr induces NFAT to prime non-activated T cells for productive infection

Open Biology ◽  
2016 ◽  
Vol 6 (7) ◽  
pp. 160046 ◽  
Author(s):  
Kristin Höhne ◽  
Ramona Businger ◽  
Anouk van Nuffel ◽  
Sebastian Bolduan ◽  
Herwig Koppensteiner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Productive Infection ◽  
Cell Infection ◽  
Viral Reservoirs ◽  
Activated T Cells ◽  
Cycle Arrest ◽  
Nfat Activation ◽  
Mediate Cell ◽  
Hiv 1

The majority of T cells encountered by HIV-1 are non-activated and do not readily allow productive infection. HIV-1 Vpr is highly abundant in progeny virions, and induces signalling and HIV-1 LTR transcription. We hence hypothesized that Vpr might be a determinant of non-activated T-cell infection. Virion-delivered Vpr activated nuclear factor of activated T cells (NFAT) through Ca 2+ influx and interference with the NFAT export kinase GSK3β. This leads to NFAT translocation and accumulation within the nucleus and was required for productive infection of unstimulated primary CD4 + T cells. A mutagenesis approach revealed correlation of Vpr-mediated NFAT activation with its ability to enhance LTR transcription and mediate cell cycle arrest. Upon NFAT inhibition, Vpr did not augment resting T-cell infection, and showed reduced G2/M arrest and LTR transactivation. Altogether, Vpr renders unstimulated T cells more permissive for productive HIV-1 infection and stimulates activation of productively infected as well as virus-exposed T cells. Therefore, it could be involved in the establishment and reactivation of HIV-1 from viral reservoirs and might have an impact on the levels of immune activation, which are determinants of HIV-1 pathogenesis.

scholarly journals Longitudinal Analysis of Peripheral and Colonic CD161+ CD4+ T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1426
Author(s):  
Kerri Lal ◽  
Yuwadee Phuang-Ngern ◽  
Suchada Suhkumvittaya ◽  
Edwin Leeansyah ◽  
Aljawharah Alrubayyi ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cell Population ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Acute Hiv ◽  
Hiv 1

CD161 expression on CD4+ T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161+ CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161+ CD4+ T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161+ CD4+ T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161+ CD4+ T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161+ CD4+ T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161+ CD4+ T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161+ CD4+ T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161+ CD4+ T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161+ CD4+ T cell population that could not be completely prevented by the initiation of ART.

scholarly journals Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

2005 ◽  
Vol 79 (5) ◽  
pp. 3195-3199 ◽  
Author(s):  
Jean-Daniel Lelièvre ◽  
Frédéric Petit ◽  
Damien Arnoult ◽  
Jean-Claude Ameisen ◽  
Jérôme Estaquier
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Infection ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

scholarly journals Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

2008 ◽  
Vol 2 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Naveed Gulzar ◽  
Sowyma Balasubramanian ◽  
Greg Harris ◽  
Jaime Sanchez-Dardon ◽  
Karen F.T. Copeland
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Proliferative Response ◽  
Cell Infection ◽  
Cellular Target ◽  
Potential Reservoir ◽  
Infected Cells ◽  
Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

scholarly journals HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

2019 ◽  
Vol 16 (4) ◽  
pp. 302-314
Author(s):  
Chinnambedu Ravichandran Swathirajan ◽  
Ramachandran Vignesh ◽  
Greer Waldrop ◽  
Uma Shanmugasundaram ◽  
Pannerselvam Nandagopal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Activation Rates ◽  
Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

scholarly journals Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract

2004 ◽  
Vol 200 (6) ◽  
pp. 761-770 ◽  
Author(s):  
Saurabh Mehandru ◽  
Michael A. Poles ◽  
Klara Tenner-Racz ◽  
Amir Horowitz ◽  
Arlene Hurley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Cell Loss ◽  
Cd4 T Cell ◽  
Suppressive Therapy ◽  
Hiv 1 ◽  
Gi Mucosa

Given its population of CCR5-expressing, immunologically activated CD4+ T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4+ T cells would be observed in HIV-1–infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4+ T cells compared with peripheral blood CD4+ T cells is seen during primary HIV-1 infection. CD4+ T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4+ T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.

Feasibility of a Stem Cell Gene Therapy Approach with Nonmyeloablative Conditioning in Patients with HIV-1 Infection.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 412-412
Author(s):  
Gian-Paolo Rizzardi ◽  
Silvia Nozza ◽  
Lucia Turchetto ◽  
Alexandre Harari ◽  
Giuseppe Tambussi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Cd34 Cells ◽  
Ifn Γ ◽  
Cell Gene ◽  
Stem Cell Gene ◽  
Hiv 1

Abstract Several reasons warrant the development of innovative therapeutic strategies for HIV/AIDS. These include the inability of highly active antiretroviral therapy (HAART) to eradicate the virus, the HAART-induced severe long-term toxicity occurring in patients, the development of HAART-resistant HIV-1 strains in the host, and the lack of an efficacious vaccine. Genetic engineering of hematopoietic stem cells (HSC) combined with nonmyeloablative conditioning proved safety and efficacy in the treatment of adenosine deaminase-deficient severe combined immunodeficiency. The feasibility of such an approach in HIV-1 infection remains, however, to be determined. In an open-label prospective trial, 18 patients with HIV-1 infection (mean±SE age 35.7±1.2, range 18.9–40; HAART since at least 3 months; CD4+ T cell counts >200/μl) have been enrolled in a HSC retroviral vector gene therapy trial using RevM10 and polAS as anti-HIV genes. Nine patients received fresh transduced CD34+ cells and all study treatments, including CD34+ cell mobilisation with G-CSF (10 μg/kg/day for 5 days), CD34+ cell collection through aphaeresis, and nonmyeloablative conditioning (1.8 g/m2 cyclophosphamide [CY]), while 9 did not undergo all study phases. All patients have been followed-up for at least 48 weeks. Mean±SE baseline CD4+ T cell counts were 577±42, while plasma HIV-1 RNA levels (VL) were below the limit of detection (80 copies/ml) of the assay (Nasba Organon) in 9 out of 18 patients. CD34+ cells were efficiently mobilized and collected from patients with HIV-1 infection, achieving 4.42±0.64 x 106 CD34+ cells/kg after purification (CliniMACS, Miltenyi Biotec), and 3.93±1.2 x 106 viable CD34+ cells/kg in the infusion product, 30% of which were transduced CD34+ cells. It is worth noting that 1) effective VL suppression significantly increased the yields of mobilization, purification and transduction processes, and 2) peripheral blood CD34+ cell counts before aphaeresis (mean, 72 cells/μl) predicted the number of viable CD34+ cells infused (β 0.722, 95% CI 0.007–0.092, P=0.028, regression analysis), and a cut-off value >30 CD34+ cells/μl predicted the success of all procedures (P=0.018, χ2 analysis, Fisher’s exact test). Gene marking levels, predicted by the number of transduced cells infused, were detectable in all patients, though they significantly decreased over time. CY conditioning caused a marked decrease in CD4+ T cell counts, restored over long-term follow-up. This recovery correlated with levels of CD4+ TCR-rearrangement excision circles and CD4+CD45RA+CCR7+ naïve T cells, indicating thymus regeneration capacity in >30-year-old patients with HIV-1 infection. Importantly, CMV-specific IL-2- and IFN- γ-secreting CD4+CD69+ T cells were able to expand while no clinically relevant CMV reactivation occurred; moreover, proportions of IL-2, IL-2/IFN- γ, and IFN-γ-secreting HSV, TT, and EBV-specific CD4+ T cells were not altered by CY over time. These data indicate that effective stem cell gene transfer is feasible in patients with HIV-1 infection, and suggest the use of non-lymphocyte-toxic conditioning regimen, such as busulfan.

Elevated levels of CD4+CD7− T cells in HIV infection add to the prognostic value of low CD4 T cell levels and HIV-1-RNA quantification

AIDS ◽  
2001 ◽  
Vol 15 (18) ◽  
pp. 2459-2460 ◽  
Author(s):  
Javier Carbone ◽  
Juana Gil ◽  
José M. Benito ◽  
Angeles Muñóz-Fernández ◽  
Eduardo Fernández-Cruz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Prognostic Value ◽  
Cd4 T Cell ◽  
Rna Quantification ◽  
Hiv 1

scholarly journals The Cell Tropism of Human Immunodeficiency Virus Type 1 Determines the Kinetics of Plasma Viremia in SCID Mice Reconstituted with Human Peripheral Blood Leukocytes

1998 ◽  
Vol 72 (3) ◽  
pp. 2002-2009 ◽  
Author(s):  
Gastón R. Picchio ◽  
Richard J. Gulizia ◽  
Kathy Wehrly ◽  
Bruce Chesebro ◽  
Donald E. Mosier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Peripheral Blood ◽  
Viral Rna ◽  
Cell Tropism ◽  
Blood Leukocytes ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Rna Levels

ABSTRACT Most individuals infected with human immunodeficiency virus type 1 (HIV-1) initially harbor macrophage-tropic, non-syncytium-inducing (M-tropic, NSI) viruses that may evolve into T-cell-tropic, syncytium-inducing viruses (T-tropic, SI) after several years. The reasons for the more efficient transmission of M-tropic, NSI viruses and the slow evolution of T-tropic, SI viruses remain unclear, although they may be linked to expression of appropriate chemokine coreceptors for virus entry. We have examined plasma viral RNA levels and the extent of CD4+ T-cell depletion in SCID mice reconstituted with human peripheral blood leukocytes following infection with M-tropic, dual-tropic, or T-tropic HIV-1 isolates. The cell tropism was found to determine the course of viremia, with M-tropic viruses producing sustained high viral RNA levels and sparing some CD4+ T cells, dual-tropic viruses producing a transient and lower viral RNA spike and extremely rapid depletion of CD4+T cells, and T-tropic viruses causing similarly lower viral RNA levels and rapid-intermediate rates of CD4+ T-cell depletion. A single amino acid change in the V3 region of gp120 was sufficient to cause one isolate to switch from M-tropic to dual-tropic and acquire the ability to rapidly deplete all CD4+ T cells.

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