scholarly journals Prolonged Post-Treatment Virologic Control and Complete Seroreversion after Advanced HIV-1 Infection

2020 ◽  
Author(s):  
Analia Uruena ◽  
Isabel Cassetti ◽  
Neena Kashyap ◽  
Claire Deleage ◽  
Jacob D Estes ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Mononuclear Cells ◽  
Brain Biopsy ◽  
Post Treatment ◽  
Hiv Diagnosis ◽  
Hiv Reservoir ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Hiv 1

Abstract Background Possible human immunodeficiency virus (HIV)-1 clearance has been rarely reported. Here we describe a unique case of an HIV-positive, combination antiretroviral therapy (cART)-experienced woman with prior acquired immunodeficiency syndrome (AIDS) who has not experienced viral rebound for over 12 years since discontinuing cART. Methods Leukapheresis, colonoscopy, and lymph node excision were performed for detailed examination of virologic (including HIV reservoir) and immunologic features. Comparisons were made with chronically infected patients and healthy controls. Results No HIV-specific antibodies were detected in serum. Plasma HIV RNA levels were <0.2 copies/mL and, except for low-frequency HIV DNA + cells in lymph node tissue (1 copy/3 x 10 6 cells), HIV antigen could not be detected by quantitative virus outgrowth (<0.0025 infectious units/10 6 CD4 + T cells) or by most measurements of HIV RNA or DNA in blood, lymph node or gut-associated mononuclear cells. HIV-specific T-cell responses were detectable, but low. Brain imaging revealed a prior biopsy site and persistent white matter disease since 1996. HIV DNA + cells in the 1996 brain biopsy specimen confirmed her identity and initial HIV diagnosis. Conclusions This represents the first report of complete seroreversion, prolonged post-treatment virus suppression, a profoundly small HIV reservoir and persistent HIV-specific T cells in an adult with prior AIDS.

scholarly journals Defective HIV-1 proviruses produce viral proteins

2020 ◽  
Vol 117 (7) ◽  
pp. 3704-3710 ◽  
Author(s):  
Hiromi Imamichi ◽  
Mindy Smith ◽  
Joseph W. Adelsberger ◽  
Taisuke Izumi ◽  
Francesca Scrimieri ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Viral Proteins ◽  
Open Reading Frames ◽  
Peripheral Blood Mononuclear ◽  
Hiv Rna ◽  
Rna Transcripts ◽  
Extracellular Virus ◽  
Hiv 1

HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as “defective” by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant “graveyard” of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cell–cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.

scholarly journals HIV-DNA undetectability during chronic HIV infection: frequency and predictive factors

2020 ◽  
Vol 75 (10) ◽  
pp. 2994-2997
Author(s):  
Silvia Nozza ◽  
Laura Galli ◽  
Nicola Gianotti ◽  
Mariarita Parisi ◽  
Andrea Poli ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Undetectable Viral Load ◽  
People Living With Hiv ◽  
Infection Frequency ◽  
Hiv Diagnosis ◽  
Cross Sectional ◽  
Infected People ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Hiv 1

Abstract Background HIV-DNA is a marker of HIV reservoirs. Objectives of the study were to determine prevalence of HIV-DNA &lt; 100 copies/106 PBMCs in blood and to identify factors associated with this in a cohort of HIV-1-infected subjects treated with ART and with undetectable viral load (VL). Methods This was a cross-sectional study on chronic HIV-1-infected people living with HIV (PLWH) followed up at the Department of Infectious Diseases of San Raffaele Scientific Institute on current ART without change for 12 months, with available pre-ART HIV-RNA and with undetectable VL for ≥12 months. HIV-DNA was amplified and quantified by real-time PCR (ABI Prism 7900); limit of detectability was 100 copies/106 PBMCs. Logistic regression was used to identify predictive factors for HIV-DNA &lt; 100 copies/106 PBMCs. Results Four hundred and sixty-eight PLWH were considered in the analyses, 119 (25%) with HIV-DNA &lt; 100 copies/106 PBMCs. At multivariate analysis, we found that PLWH with lower zenith HIV-RNA, higher nadir CD4 and a shorter time between HIV diagnosis and ART start were more likely to have HIV-DNA &lt; 100 copies/106 PBMCs, after adjustment for age, gender, calendar year of ART start, type of current ART regimen, percentage time spent with undetectable VL since ART start, current CD4 and CD4/CD8 ratio. Conclusions In our chronic PLWH on virological suppression for 4 years, the prevalence of HIV-DNA &lt; 100  copies/106 PBMCs was found to be 25%. Lower zenith HIV-RNA, shorter time between HIV diagnosis and starting ART and higher CD4 nadir were independently associated with low HIV-DNA.

scholarly journals Non-Macrophage-Tropic Human Immunodeficiency Virus Type 1 R5 Envelopes Predominate in Blood, Lymph Nodes, and Semen: Implications for Transmission and Pathogenesis

2006 ◽  
Vol 80 (13) ◽  
pp. 6324-6332 ◽  
Author(s):  
Paul J. Peters ◽  
W. Matthew Sullivan ◽  
Maria J. Duenas-Decamp ◽  
Jayanta Bhattacharya ◽  
Chiambah Ankghuambom ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Lymph Node ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Macrophage Tropism ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) R5 isolates that predominantly use CCR5 as a coreceptor are frequently described as macrophage tropic. Here, we compare macrophage tropism conferred by HIV-1 R5 envelopes that were derived directly by PCR from patient tissue. This approach avoids potentially selective culture protocols used in virus isolation. Envelopes were amplified (i) from blood and semen of adult patients and (ii) from plasma of pediatric patients. The phenotypes of these envelopes were compared to those conferred by an extended panel of envelopes derived from brain and lymph node that we reported previously. Our results show that R5 envelopes vary by up to 1,000-fold in their capacity to confer infection of primary macrophages. Highly macrophage-tropic envelopes were predominate in brain but were infrequent in semen, blood, and lymph node samples. We also confirmed that the presence of N283 in the C2 CD4 binding site of gp120 is associated with HIV-1 envelopes from the brain but absent from macrophage-tropic envelopes amplified from blood and semen. Finally, we compared infection of macrophages, CD4+ T cells, and peripheral blood mononuclear cells (PBMCs) conferred by macrophage-tropic and non-macrophage-tropic envelopes in the context of full-length replication competent viral clones. Non-macrophage-tropic envelopes conferred low-level infection of macrophages yet infected CD4+ T cells and PBMCs as efficiently as highly macrophage-tropic brain envelopes. The lack of macrophage tropism for the majority of the envelopes amplified from lymph node, blood, and semen is striking and contrasts with the current consensus that R5 primary isolates are generally macrophage tropic. The extensive variation in R5 tropism reported here is likely to have an important impact on pathogenesis and on the capacity of HIV-1 to transmit.

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

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&lt;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&lt;0.0001; Adolescents: 2.25 vs 2.74log, p&lt;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.

Evidence for late stage compartmentalization of HIV-1 resistance mutations between lymph node and peripheral blood mononuclear cells

AIDS ◽  
2000 ◽  
Vol 14 (15) ◽  
pp. 2273-2281 ◽  
Author(s):  
Da' N. Haddad ◽  
Christopher Birch ◽  
Tracy Middleton ◽  
Dominic E. Dwyer ◽  
Anthony L. Cunningham ◽  
...  
Keyword(s):  
Lymph Node ◽  
Peripheral Blood Mononuclear Cells ◽  
Late Stage ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Resistance Mutations ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Hiv 1

scholarly journals ABX464 decreases the total HIV reservoir and HIV transcription initiation in CD4 + T cells from HIV-infected ART-suppressed individuals

2021 ◽  
Author(s):  
Sara Moron-Lopez ◽  
Silvia Bernal ◽  
Joseph K Wong ◽  
Javier Martinez-Picado ◽  
Steven A Yukl
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Transcription Initiation ◽  
Digital Pcr ◽  
Fold Change ◽  
Hiv Rna ◽  
Hiv Transcription ◽  
Hiv Dna ◽  
Median Level ◽  
Term Administration

Abstract Background Antiretroviral therapy (ART) intensification and disruption of latency have been suggested as strategies to eradicate HIV. ABX464 is a novel antiviral that inhibits HIV RNA biogenesis. We investigated the effect of ABX464 on HIV transcription and total and intact HIV DNA in CD4 + T cells from ART-suppressed participants enrolled in the ABIVAX-005 clinical trial (NCT02990325). Methods Peripheral CD4 + T cells were available for analysis from nine ART-suppressed participants who were treated daily with 150mg of ABX464 for 4 weeks. Total and intact HIV DNA, and initiated, 5’elongated, unspliced, polyadenylated and multiply-spliced HIV transcripts, were quantified at weeks 0, 4 and 8 using droplet digital PCR. Results We observed a significant decrease in total HIV DNA (p=0.008, median fold-change=0.8) and a lower median level of intact HIV DNA (p=n.s., median fold-change=0.8) after ABX464 treatment (wk 0 vs. 4). Moreover, we observed a decrease in initiated HIV RNA per million CD4 + T cells and per provirus (p=0.05, median fold-change=0.7; p=0.004, median fold-change=0.5, respectively), a trend towards a decrease in the 5’elongated HIV RNA per provirus (p=0.07, median fold-change=0.5), and a lower median level of unspliced HIV RNA (p=n.s., median fold-change=0.6), but no decrease in polyadenylated or multiply-spliced HIV RNA. Conclusion In this substudy, ABX464 had a dual effect of decreasing total HIV DNA (and possibly intact proviruses) and decreasing the amount of HIV transcription per provirus. To further characterize its specific mechanism of inhibiting HIV transcription, long-term administration of ABX464 should be studied in a larger cohort.

scholarly journals Selection following isolation of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and herpesvirus saimiri-transformed T cells is comparable

2002 ◽  
Vol 83 (6) ◽  
pp. 1343-1352 ◽  
Author(s):  
Natalie N. Zheng ◽  
Cherelyn Vella ◽  
Philippa J. Easterbrook ◽  
Rod S. Daniels
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Herpesvirus Saimiri ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Hiv 1

In attempts to improve isolation rates and virus yields for human immunodeficiency virus (HIV), the use of herpesvirus saimiri-immortalized T cells (HVS T cells) has been investigated as an alternative to/improvement over peripheral blood mononuclear cells (PBMCs). Here we characterize isolates rescued, in the two cell types, from two asymptomatic, long-term non-progressing HIV-1-infected individuals. All rescued viruses replicated in PBMCs and HVS T cells only, displaying a non-syncytium inducing (NSI) phenotype, and using CCR5 as co-receptor. Furthemore, PBMC/HVS T cell virus pairs displayed similar neutralization profiles. Full-length, expression-competent env genes were rescued from all virus isolates and directly from the patient samples using proviral DNA and viral RNA as templates. Compared with the sequences retrieved directly from the patient samples, both cell types showed similar selection characteristics. Whilst the selections were distinct for individual patient samples, they shared a common characteristic in selecting for viruses with increased negative charge across the V2 domain of the viral glycoproteins. The latter was observed at the env gene sequencing level for three other patients whose HIV strains were isolated in PBMCs only. This further supports a common selection for viral sequences that display a macrophage-tropic/NSI phenotype and shows that HVS T cells are a viable alternative to PBMCs for HIV-1 isolation.

scholarly journals HIV-1 Transcription but Not Intact Provirus Levels are Associated With Systemic Inflammation

2020 ◽  
Author(s):  
Alex Olson ◽  
Carolyn Coote ◽  
Jennifer E Snyder-Cappione ◽  
Nina Lin ◽  
Manish Sagar
Keyword(s):  
Infected Cell ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Rna Expression ◽  
Peripheral Blood Mononuclear ◽  
Hiv Dna ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Hiv 1 ◽  
D Dimer

Abstract Individuals infected with human immunodeficiency virus (HIV) 1 have increased inflammation, which has been associated with age-associated diseases. Plasma markers, cell-associated virus levels, and ability to stimulate RNA transcription in latently infected cell lines was examined in younger and older HIV-1–infected individuals with suppressed virus. Cell-associated RNA, but not intact provirus level, had positive correlation with plasma D-dimer levels. Compared with the younger group, the older group had higher D-dimer levels and a trend toward more cell-associated RNA but similar levels of intact proviruses. Even though all measured inflammatory markers were relatively higher in the older group, this greater inflammation did not induce more HIV-1 transcription in latently infected cell lines. Inflammation and HIV-1 RNA expression increase with age despite similar levels of intact infectious HIV DNA. While plasma inflammation is correlated with HIV-1 RNA expression in peripheral blood mononuclear cells, it does not induce HIV-1 transcription in latently infected cell lines.

Characterization of drug resistance and the defective HIV reservoir in virally suppressed vertically infected children in Mali

2020 ◽  
Vol 75 (5) ◽  
pp. 1272-1279
Author(s):  
Josephine Brice ◽  
Mariam Sylla ◽  
Nathalie Desire ◽  
Sophie Sayon ◽  
Fatoumata Telly ◽  
...  
Keyword(s):  
Stop Codon ◽  
Dried Blood Spots ◽  
Viral Population ◽  
Genotypic Resistance ◽  
Hiv Reservoir ◽  
Hiv Dna ◽  
Art Initiation ◽  
High Prevalence ◽  
Resistance Patterns ◽  
Hiv 1

Abstract Background In the perspective of ART-free HIV remission, vertically infected children treated with suppressive ART from early infancy represent an optimal population model to better understand the genetic complexity of the reservoir. Objectives To evaluate the proportion of defective viral population and the genotypic resistance patterns in cell-associated HIV DNA. Methods In a cohort including 93 ART-treated vertically HIV-infected (VHIV) children in Mali with plasma HIV-1 RNA ≤50 copies/mL for at least 6 months, we studied total HIV DNA, percentage of defective genomes and resistance by reverse transcriptase and protease bulk sequencing from whole blood in dried blood spots. Results Children had a median age of 9.9 years at the time of inclusion (IQR = 7.6–13.4) and 3.3 years (IQR = 2–7) at ART initiation; median ART duration was 5.5 years (IQR = 3.7–7.3). The median level of total HIV DNA was 470 copies/106 cells with one patient presenting undetectable HIV DNA (&lt;66 copies/106 cells). We observed the presence of at least one stop codon in viruses from 34 patients (37%). The presence of stop codons was not correlated with the level of HIV DNA or duration of ART. We showed a high prevalence of HIV-1 resistance in DNA with 26% of children harbouring virus resistant to at least one NRTI and 40% to at least one NNRTI. Conclusions While these VHIV children were successfully treated for a long time, they showed high prevalence of resistance in HIV DNA and a moderate defective HIV reservoir.

scholarly journals Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4+T Cell Activation during Antiretroviral Treatment

2014 ◽  
Vol 88 (14) ◽  
pp. 7818-7827 ◽  
Author(s):  
Sara Gianella ◽  
Marta Massanella ◽  
Douglas D. Richman ◽  
Susan J. Little ◽  
Celsa A. Spina ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Immune Activation ◽  
Genital Tract ◽  
Cell Activation ◽  
Future Studies ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Dna Reservoir

ABSTRACTAsymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4+T cells in blood (P< 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4+T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P= 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P= 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4+(P< 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations.IMPORTANCEAlmost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies.

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