Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

ABSTRACT In individuals with HIV-1 infection, depletion of CD4 + T cells is often accompanied by a malfunction of CD8 + T cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well documented, the same does not apply to CD8 counts. Here, we examined the CD8 counts in a cohort of 497 Africans with primary HIV-1 infection evaluated in monthly to quarterly follow-up visits for up to 3 years in the absence of antiretroviral therapy. Statistical models revealed that (i) CD8 counts were relatively steady in the 3- to 36-month period of infection and similar between men and women; (ii) neither geography nor heterogeneity in the HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort ( P > 0.25 in all tests); and (iii) factors independently associated with relatively high CD8 counts included demographics (age ≤ 40 years, adjusted P = 0.010) and several human leukocyte antigen class I (HLA-I) alleles, including HLA-A*03:01 ( P = 0.013), B*15:10 ( P = 0.007), and B*58:02 ( P < 0.001). Multiple sensitivity analyses provided supporting evidence for these novel relationships. Overall, these findings suggest that factors associated with the CD8 count have little overlap with those previously reported for other HIV-1-related outcome measures, including viral load, CD4 count, and CD4/CD8 ratio. IMPORTANCE Longitudinal data from 497 HIV-1 seroconverters allowed us to systematically evaluate the dynamics and correlates of CD8 + T-cell counts during untreated primary HIV-1 infection in eastern and southern Africans. Our findings suggest that individuals with certain HLA-I alleles, including A*03 (exclusively A*03:01), persistently maintain relatively high CD8 counts following HIV-1 infection, a finding which may offer an intriguing explanation for the recently reported, negative association of A*03 with HIV-1-specific, broadly neutralizing antibody responses. In future studies, attention to HLA-I genotyping data may benefit in-depth understanding of both cellular and humoral immunity, as well as the intrinsic balances of these types of immunity, especially in settings where there is emerging evidence of antagonism between the two arms of adaptive immunity.

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Reconstitution of Peripheral T Cells by Tissue-Derived CCR4+ Central Memory Cells Following HIV-1 Antiretroviral Therapy

Pathogens and Immunity ◽

10.20411/pai.v1i2.129 ◽

2016 ◽

Vol 1 (2) ◽

pp. 260 ◽

Cited By ~ 8

Author(s):

Yolanda D. Mahnke ◽

Kipper Fletez-Brant ◽

Irini Sereti ◽

Mario Roederer

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Cd8 T Cells ◽

Plasma Viral Load ◽

Cd4 T Cell ◽

Cell Numbers ◽

Cell Counts ◽

Hiv 1

Background. Highly active antiretroviral therapy induces clinical benefits to HIV-1 infected individuals, which can be striking in those with progressive disease. Improved survival and decreased incidence of opportunistic infections go hand in hand with a suppression of the plasma viral load, an increase in peripheral CD4+ T-cell counts, as well as a reduction in the activation status of both CD4+ and CD8+ T cells.Methods. We investigated T-cell dynamics during ART by polychromatic flow cytometry in total as well as in HIV-1-specific CD4+ and CD8+ T cells. We also measured gene expression by single cell transcriptomics to assess functional state.Results. The cytokine pattern of HIV-specific CD8+ T cells was not altered after ART, though their magnitude decreased significantly as the plasma viral load was suppressed to undetectable levels. Importantly, while CD4+ T cell numbers increased substantially during the first year, the population did not normalize: the increases were largely due to expansion of mucosal-derived CCR4+ CD4+ TCM; transcriptomic analysis revealed that these are not classical Th2-type cells.Conclusion. The apparent long-term normalization of CD4+ T-cell numbers following ART does not comprise a normal balance of functionally distinct cells, but results in a dramatic Th2 shift of the reconstituting immune system.

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

Viruses ◽

10.3390/v12121426 ◽

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.

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Reversal of the CD8+ T-Cell Exhaustion Induced by Chronic HIV-1 Infection Through Combined Blockade of the Adenosine and PD-1 Pathways

Frontiers in Immunology ◽

10.3389/fimmu.2021.687296 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jing Li ◽

Hui-Huang Huang ◽

Bo Tu ◽

Ming-Ju Zhou ◽

Wei Hu ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Cell Function ◽

T Cell Subsets ◽

Cell Counts ◽

T Cell Function ◽

Treatment Naïve ◽

Hiv 1

BackgroundTargeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8+ T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8+ T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8+ T-cell subsets in chronic HIV-1 infection remain poorly understood.MethodsThis study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8+ T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8+ T cells.ResultsThe proportions of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1+CD39+ CD8+ T cells were negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39+CD8+ T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39- counterparts. In vitro, a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells.ConclusionIn patients with chronic HIV-1 infection there are increased frequencies of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells. In treatment naïve patients, the frequencies of PD-1+CD39+ CD8+ T cells are negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients.

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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.

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Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

Nature Medicine ◽

10.1038/s41591-021-01509-0 ◽

2021 ◽

Author(s):

Kathryn E. Stephenson ◽

Boris Julg ◽

C. Sabrina Tan ◽

Rebecca Zash ◽

Stephen R. Walsh ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Adverse Events ◽

Antiviral Activity ◽

Controlled Trial ◽

Phase 1 ◽

Serious Adverse Events ◽

Double Blind ◽

Cell Counts ◽

Hiv 1

AbstractHuman immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

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Characteristics allelic of Human Leukocyte Antigen class I genotype and association with viral load and CD4 cell count in HIV-1 infected patients, Hanoi 2014 – 2016

Tạp chí Y học Dự phòng ◽

10.51403/0868-2836/2021/335 ◽

2021 ◽

Vol 31 (4) ◽

pp. 43-50

Author(s):

Tran Thi Minh Tam ◽

Nguyen Thuy Linh ◽

Phan Ha My ◽

Nguyen Thi Lan Anh

Keyword(s):

Viral Load ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Cd4 Cell Count ◽

Leukocyte Antigen ◽

Cell Counts ◽

Cd4 Cell Counts ◽

Cd4 Cell ◽

Hiv 1

Human Leukocyte Antigen (HLA) class I plays a regulatory role in cellular immune response to HIV-1 infection. The role of HLA alleles in HIV progression via viral load and CD4 cell count is well known. HLA class I is polymorphic and distributed differently by nation. This descriptive cross-sectional study was performed on 303 HIV-1 infected patients in 2014 - 2016, with aims to (i) characterize HLA class I genotype with 4-digit nomenclature and (ii) identify specifc alleles in correlate with CD4 cell counts and HIV viral load. 117 allele genotypes have been identifed, including 28 HLA-A alleles, 54 HLA-B alleles and 35 HLA-C alleles. The results showed that the most prevalent alleles in the population include A*11:01 (30.7%), B*15:02 (15.2%) and C*08:01 (17.1%). The frequency of haplotype created from these alleles is 8.4%. A*02:03, B*46:01 related to gender and ethnicity respectively. In conclusion, the study provided detailed pattern of HLA class I expression in a study population of HIV-1 infected patients and reported for the frst time the associated B*51:01, C*14:02 alleles associated to an increase in CD4 cell counts.

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X4-Tropic Latent HIV-1 Is Enriched in Peripheral Follicular Helper T Cells and Is Correlated with Disease Progression

Journal of Virology ◽

10.1128/jvi.01219-19 ◽

2019 ◽

Vol 94 (2) ◽

Cited By ~ 2

Author(s):

Fei Yu ◽

Qijuan Li ◽

Xi Chen ◽

Jun Liu ◽

Linghua Li ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Disease Progression ◽

Clinical Relevance ◽

Cell Recovery ◽

Tfh Cells ◽

Follicular Helper ◽

Cell Counts ◽

Latent Hiv ◽

Hiv 1

ABSTRACT Follicular helper T (TFH) cells have been shown to support productive human immunodeficiency virus type 1 (HIV-1) replication and to serve as a key component of the latent viral reservoir. However, the viral characteristics of this latent reservoir and the clinical relevance of this reservoir remain unclear. In this study, we assessed the tropic composition of latent viruses from peripheral TFH (pTFH), non-TFH memory, and naive CD4+ T cells from individuals with HIV-1 infections on suppressive combined antiretroviral therapy (cART). X4-tropic latent HIV-1 was preferentially enriched in pTFH cells compared to levels in the other two subsets. Interestingly, the ratio of X4-tropic latent HIV-1 in pTFH cells not only was robustly and inversely correlated with blood CD4+ T cell counts across patients but also was prognostic of CD4+ T cell recovery in individuals on long-term cART. Moreover, patients with higher X4-tropic latent HIV-1 ratios in pTFH cells showed greater risks of opportunistic coinfections. These findings reveal the characteristics of latent HIV-1 in TFH cells and suggest that the ratio of X4-tropic latent HIV-1 in pTFH cells is a valuable indicator for disease progression and cART efficacy. IMPORTANCE TFH cells have been shown to harbor a significant amount of latent HIV-1; however, the viral characteristics of this reservoir and its clinical relevance remain largely unknown. In this study, we demonstrate that X4-tropic latent HIV-1 is preferentially enriched in pTFH cells, which also accurately reflects the viral tropism shift. The ratio of X4-tropic proviruses in pTFH cells but not in other memory CD4+ T cell subsets is inversely and closely correlated with blood CD4+ T cell counts and CD4+ T cell recovery rates with cART. Our data suggest that the ratio of X4-tropic provirus in peripheral TFH cells can be easily measured and reflects disease progression and treatment outcomes during cART.

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

Blood ◽

10.1182/blood.v104.11.412.412 ◽

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.

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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.

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