CD8+ T-Cell Mediated Control of HIV-1 in a Unique Cohort With Low Viral Loads

A unique population of HIV-1 infected individuals can control infection without antiretroviral therapy. These individuals fall into a myriad of categories based on the degree of control (low or undetectable viral load), the durability of control over time and the underlying mechanism (i.e., possession of protective HLA alleles or the absence of critical cell surface receptors). In this study, we examine a cohort of HIV-1 infected individuals with a documented history of sustained low viral loads in the absence of therapy. Through in vitro analyses of cells from these individuals, we have determined that infected individuals with naturally low viral loads are capable of controlling spreading infection in vitro in a CD8+ T-cell dependent manner. This control is lost when viral load is suppressed by antiretroviral therapy and correlates with a clinical CD4:CD8 ratio of <1. Our results support the conclusion that HIV-1 controllers with low, but detectable viral loads may be controlling the virus due to an effective CD8+ T-cell response. Understanding the mechanisms of control in these subjects may provide valuable understanding that could be applied to induce a functional cure in standard progressors.

Download Full-text

STING and cGAS gene expressions were downregulated among HIV-1-infected persons after antiretroviral therapy

Virology Journal ◽

10.1186/s12985-021-01548-6 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Lorena Leticia Peixoto de Lima ◽

Allysson Quintino Tenório de Oliveira ◽

Tuane Carolina Ferreira Moura ◽

Ednelza da Silva Graça Amoras ◽

Sandra Souza Lima ◽

...

Keyword(s):

Gene Expression ◽

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Count ◽

Enzyme Linked Immunosorbent Assay ◽

Type I ◽

Α Level ◽

The Impact ◽

Hiv 1

Abstract Background The HIV-1 epidemic is still considered a global public health problem, but great advances have been made in fighting it by antiretroviral therapy (ART). ART has a considerable impact on viral replication and host immunity. The production of type I interferon (IFN) is key to the innate immune response to viral infections. The STING and cGAS proteins have proven roles in the antiviral cascade. The present study aimed to evaluate the impact of ART on innate immunity, which was represented by STING and cGAS gene expression and plasma IFN-α level. Methods This cohort study evaluated a group of 33 individuals who were initially naïve to therapy and who were treated at a reference center and reassessed 12 months after starting ART. Gene expression levels and viral load were evaluated by real-time PCR, CD4+ and CD8+ T lymphocyte counts by flow cytometry, and IFN-α level by enzyme-linked immunosorbent assay. Results From before to after ART, the CD4+ T cell count and the CD4+/CD8+ ratio significantly increased (p < 0.0001), the CD8+ T cell count slightly decreased, and viral load decreased to undetectable levels in most of the group (84.85%). The expression of STING and cGAS significantly decreased (p = 0.0034 and p = 0.0001, respectively) after the use of ART, but IFN-α did not (p = 0.1558). Among the markers evaluated, the only markers that showed a correlation with each other were STING and CD4+ T at the time of the first collection. Conclusions ART provided immune recovery and viral suppression to the studied group and indirectly downregulated the STING and cGAS genes. In contrast, ART did not influence IFN-α. The expression of STING and cGAS was not correlated with the plasma level of IFN-α, which suggests that there is another pathway regulating this cytokine in addition to the STING–cGAS pathway.

Download Full-text

Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ TEMRA Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict the Subsequent Viral Load Set Point

Journal of Virology ◽

10.1128/jvi.00045-07 ◽

2007 ◽

Vol 81 (11) ◽

pp. 5759-5765 ◽

Cited By ~ 52

Author(s):

John W. Northfield ◽

Christopher P. Loo ◽

Jason D. Barbour ◽

Gerald Spotts ◽

Frederick M. Hecht ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Absolute Number ◽

T Cell Response ◽

Effector Memory ◽

Set Point ◽

Effector Memory T Cells ◽

Viral Load Set Point ◽

Hiv 1

ABSTRACT CD8+ T cells are believed to play an important role in the control of human immunodeficiency virus type 1 (HIV-1) infection. However, despite intensive efforts, it has not been possible to consistently link the overall magnitude of the CD8+ T-cell response with control of HIV-1. Here, we have investigated the association of different CD8+ memory T-cell subsets responding to HIV-1 in early infection with future control of HIV-1 viremia. Our results demonstrate that both a larger proportion and an absolute number of HIV-1-specific CD8+ CCR7− CD45RA+ effector memory T cells (TEMRA cells) were associated with a lower future viral load set point. In contrast, a larger absolute number of HIV-1-specific CD8+ CCR7− CD45RA− effector memory T cells (TEM) was not related to the viral load set point. Overall, the findings suggest that CD8+ TEMRA cells have superior antiviral activity and indicate that both qualitative and quantitative aspects of the CD8+ T-cell response need to be considered when defining the characteristics of protective immunity to HIV-1.

Download Full-text

Dendritic cells transduced by multiply deleted HIV-1 vectors exhibit normal phenotypes and functions and elicit an HIV-specific cytotoxic T-lymphocyte response in vitro

Blood ◽

10.1182/blood.v96.4.1327 ◽

2000 ◽

Vol 96 (4) ◽

pp. 1327-1333 ◽

Cited By ~ 105

Author(s):

Andreas Gruber ◽

June Kan-Mitchell ◽

Kelli L. Kuhen ◽

Tetsu Mukai ◽

Flossie Wong-Staal

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Ex Vivo ◽

T Cell Response ◽

Adoptive T Cell Therapy ◽

Cytotoxic T Cell ◽

T Cell Therapy ◽

Hiv 1

Abstract Dendritic cells (DCs) genetically modified to continually express and present antigens may be potent physiologic adjuvants for induction of prophylactic or therapeutic immunity. We have previously shown that an env and nef deleted HIV-1 vector (HIV-1ΔEN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34+ precursors of DCs. Here we extended these findings with HIV-1ΔEN to highly differentiated human DCs derived in culture from circulating monocytes (DCs). In addition, a new vector derived from HIV-1ΔEN but further deleted in its remaining accessory genes vif, vpr, and vpu(HIV-1ΔEN V3) was also tested. Both vectors efficiently transduced DCs. Transduction of DCs did not significantly alter their viability or their immunophenotype when compared with untransduced DCs. Furthermore, the phagocytic potential of immature DCs, as well as their ability to differentiate into mature DCs capable of stimulating T-cell proliferation, was not affected. Finally, DCs transduced by the HIV-1ΔEN vector were able to elicit a primary antiviral cytotoxic T-cell response in autologous CD8 T cells. These results suggest that HIV-1–based vectors expressing viral antigens may be useful for in vivo active immunization as well as ex vivo priming of cytotoxic T cells for adoptive T-cell therapy.

Download Full-text

Cumulative viral load as a predictor of CD4+ T-cell response to antiretroviral therapy using Bayesian statistical models

PLoS ONE ◽

10.1371/journal.pone.0224723 ◽

2019 ◽

Vol 14 (11) ◽

pp. e0224723 ◽

Cited By ~ 1

Author(s):

Joseph B. Sempa ◽

Theresa M. Rossouw ◽

Emmanuel Lesaffre ◽

Martin Nieuwoudt

Keyword(s):

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Response ◽

Statistical Models ◽

T Cell Response ◽

Cd4 T Cell

Download Full-text

Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy

HIV Medicine ◽

10.1111/j.1468-1293.2004.00188.x ◽

2004 ◽

Vol 5 (2) ◽

pp. 74-81 ◽

Cited By ~ 17

Author(s):

F van Leth ◽

FWNM Wit ◽

P Reiss ◽

JKME Schattenkerk ◽

ME van der Ende ◽

...

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

Protease Inhibitor ◽

Cell Response ◽

Highly Active Antiretroviral Therapy ◽

T Cell Response ◽

Cd4 T Cell ◽

Highly Active ◽

Hiv 1

Download Full-text

Photopheresis in HIV-1 Infected Patients (Pt) Using Benzoporphyrin Derivative (BPD-MA) Induces Apoptosis in CD4 Cells, Increases Cytolytic T-Cell Activity, Intracellular Expression of Chemokines, and Decreases HIV Infectivity and Viral Load.

Blood ◽

10.1182/blood.v108.11.1257.1257 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1257-1257

Author(s):

Zale P. Bernstein ◽

Thomas Dougherty ◽

Stanley Schwartz ◽

Sandra Gollnick ◽

Carleton Stewart ◽

...

Keyword(s):

Viral Load ◽

Immune System ◽

T Cell ◽

Ex Vivo ◽

Cell Activity ◽

Area Under The Curve ◽

Viral Control ◽

Viral Loads ◽

Hiv 1

Abstract HIV is able to elude both cellular and humoral arms of the immune system; thereby making viral control difficult. Extra corporeal photochemotherapy (ECP) or photopheresis is an immunomodulatory therapy in which lymphocytes are reinfused into the host after exposure to a photoactive compound and ultraviolet A light. It is an effective therapeutic approach to several disorders of the immune system including acute and chronic graft-versus-host disease, scleroderma, and cutaneous T-cell lymphoma. This process may offer a novel approach to viral control with minimal or no toxicity. We initiated an ex vivo and subsequently a clinical pilot trial utilizing Benzoporphyrin Derivative as the photosensitive compound. Ex vivo dosing studies identified the minimum energy levels of light exposure and concentrations of BPD that eradicated both cell-free and cell-associated HIV-1 infectivity without destroying the virus particles or infected leukocytes. Leukocytes so treated remained viable. They did demonstrate altered cytokine and chemokine expression with apoptosis induced in a minority of CD4 but not CD8 positive cells. Furthermore, there was a statistically significant increase in cytolytic T-cell activity expressed as percentage of granzyme-B release. A pilot in vivo, 24 week clinical trial in seven HIV-1 infected patients (all were required, upon entry, to have viral loads of > 10,000) using the photopheresis parameters established above demonstrated that the treatment was well tolerated and beneficial. Three individuals who had rapidly rising viral loads prior to initiating therapy stabilized once treatment began. Two of which had a (sustained) greater than .5 log decrement and 5 had stable plasma viral loads (less than a .5 log increment or decrement) with varied effects on absolute CD4 and CD8 positive lymphocytes counts. One subject achieved a greater than 1 log decrement in HIV-1 plasma viral load also developed undetectable in vivo cell-free and cell-associated HIV-1 infectivity while demonstrating an increased in vitro lymphocyte mitogen stimulation index. Subsequently, under amended and successor protocol 5 additional 12 month courses were administered to three additional patients and two of the previous enrollees. The area under the curve for viral load (viral load x # of weeks) for these twelve courses of therapy showed a significant decrease from pre to post therapy (p 0.007). There were no significant changes in CD4 or CD8 numbers area under the curve (CD4 number # of weeks and CD8 number x # of weeks). None of the subjects developed an AIDS defining illness during the course of therapy nor were there any treatment associated toxicities. These studies suggest that ECP augments activity of various arms of the immune system without any significant toxicity and may be effective in controlling HIV replication. We now plan a randomized Phase II study utilizing long-term photopheresis (twice monthly for 48 weeks) in addition to anti-retroviral therapy versus anti-retroviral therapy alone to further determine efficacy and mechanism of activity.

Download Full-text

Long-Term Control of HIV-1 in Hemophiliacs Carrying Slow-Progressing Allele HLA-B*5101

Journal of Virology ◽

10.1128/jvi.00171-10 ◽

2010 ◽

Vol 84 (14) ◽

pp. 7151-7160 ◽

Cited By ~ 38

Author(s):

Yuka Kawashima ◽

Nozomi Kuse ◽

Hiroyuki Gatanaga ◽

Takuya Naruto ◽

Mamoru Fujiwara ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Cytotoxic T Lymphocyte ◽

T Cell Response ◽

Slow Progression ◽

Lack Of Control ◽

Escape Mutants ◽

Hiv 1

ABSTRACT HLA-B*51 alleles are reported to be associated with slow disease progression to AIDS, but the mechanism underlying this association is still unclear. In the present study, we analyzed the effect of HLA-B*5101 on clinical outcome for Japanese hemophiliacs who had been infected with HIV-1 before 1985 and had been recruited in 1998 for this study. HLA-B*5101+ hemophiliacs exhibited significantly slow progression. The analysis of HLA-B*5101-restricted HIV-1-specific cytotoxic T-lymphocyte (CTL) responses to 4 HLA-B*-restricted epitopes in 10 antiretroviral-therapy (ART)-free HLA-B*5101+ hemophiliacs showed that the frequency of Pol283-8-specific CD8+ T cells was inversely correlated with the viral load, whereas the frequencies of CD8+ T cells specific for 3 other epitopes were positively correlated with the viral load. The HLA-B*5101+ hemophiliacs whose HIV-1 replication had been controlled for approximately 25 years had HIV-1 possessing the wild-type Pol283-8 sequence or the Pol283-8V mutant, which does not critically affect T-cell recognition, whereas other HLA-B*5101+ hemophiliacs had HIV-1 with escape mutations in this epitope. The results suggest that the control of HIV-1 over approximately 25 years in HLA-B*5101-positive hemophiliacs is associated with a Pol283-8-specific CD8+ T-cell response and that lack of control of HIV-1 is associated with the appearance of Pol283-8-specific escape mutants.

Download Full-text