Impact of HLA Class I Alleles on Timing of HIV Rebound After Antiretroviral Treatment Interruption

Identifying host determinants associated with HIV reservoir size and viral rebound timing after an analytic treatment interruption (ATI) is an important step in the search for an HIV functional cure. A pooled analysis of 103 participants from four AIDS Clinical Trials Group ATI studies to identify the association between HLA class I alleles with HIV reservoir size and viral rebound timing. Total HIV DNA and cell-associated HIV RNA (CA-RNA) were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. HLA class I typing was performed and we generated an odds ratio (OR) of predicted HLA effect on HIV viremia control for each individual and compared this with time to viral rebound, and levels of HIV DNA and CA-RNA. There was no significant association between the HLA ORs and levels of HIV DNA or CA-RNA, but carriage of protective HLA-B alleles (lower OR scores) was associated with delayed viral rebound (P=0.02). Higher OR scores at the HLA-C locus were associated with longer duration of ART treatment (P=0.01) and this trend was also seen with the combined OR score (P=0.007). Individuals with protective HLA-B alleles had delayed viral rebound after treatment interruption that was not explained by differences in baseline reservoir size. The results indicate the vital role of cellular host immunity in preventing HIV rebound and the importance of taking into account the HLA status of study participants being evaluated in HIV cure trials.

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Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Journal of Virology ◽

10.1128/jvi.02139-15 ◽

2015 ◽

Vol 90 (3) ◽

pp. 1369-1376 ◽

Cited By ~ 70

Author(s):

Mary F. Kearney ◽

Ann Wiegand ◽

Wei Shao ◽

John M. Coffin ◽

John W. Mellors ◽

...

Keyword(s):

Clinical Trials ◽

Antiretroviral Therapy ◽

Opportunistic Infections ◽

Treatment Interruption ◽

Viral Rebound ◽

Proliferating Cells ◽

Peripheral Blood Mononuclear ◽

Hiv Reservoir ◽

Infected Cells ◽

Aids Clinical Trials

ABSTRACTUnderstanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2- to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIV-infected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission.IMPORTANCEAntiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV-infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that found within cells prior to treatment interruption. We found several incidences in which plasma HIV variants exactly matched that of multiple proviral DNA copies from infected blood cells sampled before treatment interruption. In addition, we found that these cells were not dormant but were generating unspliced RNA transcripts before treatment was interrupted. Identification of the HIV reservoir and determining its mechanisms for persistence may aid in the development of strategies toward a cure for HIV. (This study was presented in part at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 23 to 26 2015.)

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Initiating antiretroviral treatment early in infancy has long-term benefits on the HIV reservoir in late childhood and adolescence

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1931 ◽

2021 ◽

Author(s):

Véronique Avettand-Fenoel ◽

Jérôme Lechenadec ◽

Mariama Sadjo Diallo ◽

Marine Fillion ◽

Adeline Melard ◽

...

Keyword(s):

Mononuclear Cells ◽

Ex Vivo ◽

T Cell Subsets ◽

Effector Memory ◽

Childhood And Adolescence ◽

Older Children ◽

Peripheral Blood Mononuclear ◽

Hiv Reservoir ◽

Hiv Dna ◽

Cart Initiation

Abstract Background Early combined antiretroviral therapy (cART) limits the total HIV-DNA load in children. However, data on its impact in older children and adolescents remain scarce. This study aims to compare HIV reservoirs in children (5-12 years) and adolescents (13-17 years) who started cART before 6 months (early (E-)group) or after 2 years old (late (L-)group). Methods The ANRS-EP59-CLEAC study prospectively enrolled 76 HIV-1 perinatally-infected patients who reached HIV-RNA<400 copies/mL less than 24 months after cART initiation, regardless of subsequent viral suppression (E-group: 27 children, 9 adolescents; L-group: 19 children, 21 adolescents). Total and integrated HIV-DNA were quantified in blood and in CD4+ T cell subsets. A substudy assessed HIV reservoir inducibility after ex vivo peripheral blood mononuclear cells (PBMCs) stimulation. Results Total HIV-DNA levels were lower in early- than late-treated patients (Children: 2.14 vs 2.87 log cp/million PBMCs, p<0.0001; Adolescents: 2.25 vs 2.74log, p<0.0001). Low reservoir was independently associated with treatment precocity, protective HLA and low cumulative viremia since cART initiation. The 60 participants with undetectable integrated HIV-DNA started cART earlier than the other patients (4 vs 54 months, p=0.03). In those with sustained virological control, transitional memory and effector memory CD4+T cells were less infected in the E-group than in the L-group (p=0.03 and 0.02, respectively). Viral inducibility of reservoir cells after normalization to HIV-DNA levels was similar between the groups. Conclusions Early cART results in a smaller blood HIV reservoir until adolescence, but all tested participants had an inducible reservoir. This deserves cautious consideration for HIV remission strategies.

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IMMU-08. THE ANTIGENIC LANDSCAPE OF GLIOBLASTOMA - REFINING THE TARGETS FOR IMMUNOTHERAPY

Neuro-Oncology ◽

10.1093/neuonc/noz175.502 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi120-vi120

Author(s):

Konstantina Kapolou ◽

Lena Katharina Freudenmann ◽

Ekaterina Friebel ◽

Leon Bichmann ◽

Burkhard Becher ◽

...

Keyword(s):

Cell Lines ◽

Mononuclear Cells ◽

Hla Class I ◽

Class Ii ◽

Class I ◽

Reference Database ◽

Isocitrate Dehydrogenase 1 ◽

Peripheral Blood Mononuclear ◽

Primary Glioblastoma ◽

Hla Ligandome

Abstract We provide a comprehensive analysis of the antigenic landscape of glioblastoma using a multi-omics approach including ligandome mapping of the Human Leukocyte Antigen (HLA) ligandome, next generation sequencing (NGS) as well as an in-depth characterization of tumor-infiltrating lymphocytes (TIL) using mass cytometry and ultra-deep sequencing of the T-cell receptor (TCR). Tumor-exclusive HLA class I and class II ligands (immune precipitation and LC-MS/MS) of 24 isocitrate dehydrogenase 1 wild type glioblastoma samples and 10 autologous primary glioblastoma cell lines were defined in comparison to an HLA ligandome normal tissue reference database (n > 418). We found 11,496 glioblastoma exclusive HLA class I ligands (2,064 shared with cell lines; 3,754 on ≥ 2 glioblastoma samples). On the source protein level, 239 glioblastoma exclusive proteins were identified; among them 54 were also found in cell lines. For HLA class II ligands the analysis revealed 11,870 glioblastoma exclusive peptides (444 shared with cell lines; 3,420 on ≥ 2 glioblastoma samples) and 278 glioblastoma exclusive proteins; among which 18 were present also in cell lines. Moreover, whole-exome sequencing and whole RNA sequencing of 13 tumor samples was performed with the aim to predict neoantigens. On average 5,662 somatic missense effects were identified per patient (min: 4,258; max: 7,479). Candidate peptides are grouped into (i) in silico predicted neoepitopes, (ii) tumor-exclusivity on HLA, (iii) gene expression (e.g. cancer testis antigens). Top-ranking candidates from each group will be tested with regards to their immunogenicity in an autologous setting (TIL, peripheral blood mononuclear cells, patient derived tumor cells). Finally, the peptide and immunogenicity data is correlated with the immune phenotype of the TIL compartment as well as the TCR repertoire of the sample.

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Mycobacterium tuberculosis co-infection is associated with increased surrogate marker of the HIV reservoir

AIDS Research and Therapy ◽

10.1186/s12981-020-00320-0 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Jingna Xun ◽

Tangkai Qi ◽

Lei Zou ◽

Qi Tang ◽

Yinzhong Shen ◽

...

Keyword(s):

Mononuclear Cells ◽

Surrogate Marker ◽

Baseline Viral Load ◽

People Living With Hiv ◽

Peripheral Blood Mononuclear ◽

Hiv Reservoir ◽

Hiv Dna ◽

Interleukin 7 ◽

Living With Hiv ◽

The Impact

Abstract Background Tuberculosis (Tb) is the most frequent opportunistic infection among people living with HIV infection. The impact of Tb co-infection in the establishment and maintenance of the HIV reservoir is unclear. Method We enrolled 13 HIV-infected patients with microbiologically confirmed Tb and 10 matched mono-HIV infected controls. Total HIV DNA in peripheral blood mononuclear cells (PBMCs), plasma interleukin-7 (IL-7) concentrations and the activities of indoleamine 2,3-dioxygenase (IDO) were measured for all the participants prior to therapy and after antiretroviral therapy (ART). Results After a duration of 16 (12, 22) months’ ART, patients co-infected with Tb who were cured of Tb maintained higher levels of HIV DNA compared with mono-HIV infected patients [2.89 (2.65- 3.05) log10 copies/106 cells vs. 2.30 (2.11–2.84) log10 copies/106 cells, P = 0.008]. The levels of on-ART HIV DNA were positively correlated with the baseline viral load (r = 0.64, P = 0.02) in Tb co-infected group. However, neither plasma IL-7 concentration nor plasma IDO activity was correlated with the level of on-ART HIV DNA. Conclusions Tb co-infection was associated with the increased surrogate marker of the HIV reservoir, while its mechanism warrants further examination.

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Faculty Opinions recommendation of The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725949885.793564920 ◽

2019 ◽

Author(s):

Gayle Sherman

Keyword(s):

Treatment Interruption ◽

Viral Rebound ◽

Hiv Reservoir

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HLA class I expressions on peripheral blood mononuclear cells in colorectal cancer patients

Chinese Journal of Cancer Research ◽

10.1007/s11670-012-0077-z ◽

2012 ◽

Vol 24 (1) ◽

pp. 77-82 ◽

Cited By ~ 2

Author(s):

Zhi-mian Zhang ◽

Xiao Guan ◽

Ying-jie Li ◽

Ming-chen Zhu ◽

Xiao-jing Yang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Hla Class I ◽

Class I ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells ◽

Colorectal Cancer Patients

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Analytical treatment interruption in chronic HIV-1 infection: time and magnitude of viral rebound in adults with 10 years of undetectable viral load and low HIV-DNA (APACHE study)

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz138 ◽

2019 ◽

Vol 74 (7) ◽

pp. 2039-2046 ◽

Cited By ~ 9

Author(s):

Antonella Castagna ◽

Camilla Muccini ◽

Laura Galli ◽

Alba Bigoloni ◽

Andrea Poli ◽

...

Keyword(s):

Viral Load ◽

Undetectable Viral Load ◽

Treatment Interruption ◽

Viral Reservoir ◽

Viral Rebound ◽

Analytical Treatment ◽

Hiv Rna ◽

Hiv Dna ◽

Acute Retroviral Syndrome ◽

Hiv 1

AbstractObjectivesDespite the fact that there are individuals who have chronic HIV infection, few studies have investigated ART interruption in this setting. The aim of this study was to evaluate the ability to spontaneously control viral replication during analytical treatment interruption (ATI) in adults with chronic HIV-1 infection, on ART, with suppressed viraemia for >10 years and with a low reservoir.Patients and methodsThis was a prospective, open-label, single-arm, non-randomized, proof-of-concept study (NCT03198325) of subjects with chronic HIV-1 infection, HIV-RNA <50 copies/mL for ≥10 years, without residual viraemia for ≥5 years, CD4+ >500 cells/mm3, HIV-DNA <100 copies/106 PBMCs and without comorbidities or AIDS-defining diseases. Enrolled patients were strictly monitored. The ART regimen in use at ATI was resumed in the case of confirmed viral rebound (CVR, two consecutive HIV-RNA >50 copies/mL). Results are reported as median (IQR).ResultsNine patients underwent ATI. All participants experienced CVR [4.84 (IQR: 3.47–6.47) HIV-RNA log10 copies/mL] after ATI at a median time of 21 days (range 14–56) and restarted ART. After ART resumption, all the subjects achieved HIV-RNA <50 copies/mL in a median of 88 days (range 15–197). No serious adverse event occurred; one subject experienced acute retroviral syndrome. No significant correlation between baseline factors and time to viral rebound was observed, while the magnitude of viral rebound was significantly associated with pre-ART HIV-1 RNA (Spearman r = 0.786, P = 0.036), nadir CD4+ (Spearman r = −0.800, P = 0.010), baseline CD4+ (Spearman r = −0.667, P = 0.049) and years with undetectable viral load (Spearman r = −0.717, P = 0.030).ConclusionsDespite a long period of HIV viral load suppression and a low viral reservoir, early and consistent viral rebound was observed during ATI in all subjects.

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