scholarly journals Human Immunodeficiency Virus (HIV)–Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy

2019 ◽  
Vol 221 (5) ◽  
pp. 744-755 ◽  
Author(s):  
Jenny L Anderson ◽  
Gabriela Khoury ◽  
Rémi Fromentin ◽  
Ajantha Solomon ◽  
Nicolas Chomont ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
People Living With Hiv ◽  
Hiv Persistence ◽  
Hiv Dna ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Living With Hiv

Abstract Background Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy. Methods Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry. Results Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines. Conclusions HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.

scholarly journals Interleukin-7 promotes HIV persistence during antiretroviral therapy

Blood ◽  
2013 ◽  
Vol 121 (21) ◽  
pp. 4321-4329 ◽  
Author(s):  
Claire Vandergeeten ◽  
Rémi Fromentin ◽  
Sandrina DaFonseca ◽  
Mariam B. Lawani ◽  
Irini Sereti ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Viral Latency ◽  
Absolute Number ◽  
Hiv Persistence ◽  
Hiv Dna ◽  
Interleukin 7 ◽  
Key Points ◽  
Latently Infected

Key Points IL-7 does not disrupt viral latency in highly pure resting latently infected CD4+ T cells from HIV-infected subjects receiving ART. IL-7 therapy leads to a 70% increase in the absolute number of circulating CD4+ T cells harboring integrated HIV DNA 4 weeks posttherapy.

scholarly journals Continuous Prophylactic Antiretrovirals/Antiretroviral Therapy Since Birth Reduces Seeding and Persistence of the Viral Reservoir in Children Vertically Infected With Human Immunodeficiency Virus

2020 ◽  
Author(s):  
Marta Massanella ◽  
Thanyawee Puthanakit ◽  
Louise Leyre ◽  
Thidarat Jupimai ◽  
Panadda Sawangsinth ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Cross Sectional Study ◽  
Viral Reservoir ◽  
Cross Sectional ◽  
Hiv Reservoir ◽  
Hiv Dna ◽  
Art Initiation ◽  
Immunodeficiency Virus ◽  
Infected Cells

Abstract Background Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. Methods We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. Results Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P < .020 and P < .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P < .01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during 3 years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARVs before starting ART and those who delayed ART initiation without receiving prior prophylaxis. Conclusions Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir.

scholarly journals Quality of Life People Living with HIV-AIDS (PLWHA) with Antiretroviral therapy in Cendana Clinic Ngudi Waluyo Wlingi Hospital

2015 ◽  
Vol 2 (1) ◽  
pp. 006-014
Author(s):  
Erni Setiyorini
Keyword(s):  
Quality Of Life ◽  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
People Living With Hiv ◽  
Environment Problem ◽  
Immunodeficiency Virus ◽  
Long Time ◽  
Living With Hiv ◽  
Hiv Aids

Human Immunodeficiency Virus (HIV)is desease with high mortality and everyone have chancegot HIV. At Blitar HIV/AIDS prevalence increase since 2010. The incubation of HIV need long time tobecome AIDS. At this period PLWHA faced with physic, physichologic, sosial, environment problem andimpact to their quality of life. The purpose of this study was to describe quality of life PLWHA at physic,physichologic, sosial, environment dimension. Method: Research design was descriptive. Population ofthis study is PLWHA who receiving ARV at Cendana Clinic Ngudi Waluyo Wlingi Hospital. Samples 42respondent by using convenient sampling. Data collected at September 1st– 30, 2013 by questionaire.Result of this study in physic dimension much of them at good 16 peoples (38,1%), enough and less, eachof them 13 peoples (31%). Physhicology dimension at good and enough, each of them 20 peoples(47,6%) then at less 2 peoples (4,8%). Sosial dimension enough 25 peoples (59,5%), good 15 peoples(35,7%) and less 2 peoples (4,8%). Environment dimension enough 16 peoples (38,1%), good 15peoples (35,7%) dan kurang 11 orang (26,2%). It is suggested for nurse to implementation nursing careplan to PLWHA suitable with their quality of life dimension and enhance support to their sosial activity.

scholarly journals Clonal Expansion of Infected CD4+ T Cells in People Living with HIV

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2078
Author(s):  
John M. Coffin ◽  
Stephen H. Hughes
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Large Fraction ◽  
Latent Reservoir ◽  
People Living With Hiv ◽  
Resting Cells ◽  
Hiv Rna ◽  
Art Initiation ◽  
Infected Cells ◽  
Living With Hiv

HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative strategies. The discovery that a large fraction of the persistently infected cells in individuals on suppressive ART are members of large clones greatly changed our view of the reservoir and how it arises. Rather than being the products of infection of resting cells, as was once thought, HIV persistence is largely or entirely a consequence of infection of cells that are either expanding or are destined to expand, primarily due to antigen-driven activation. Although most of the clones carry defective proviruses, some carry intact infectious proviruses; these clones comprise the majority of the reservoir. A large majority of both the defective and the intact infectious proviruses in clones of infected cells are transcriptionally silent; however, a small fraction expresses a few copies of unspliced HIV RNA. A much smaller fraction is responsible for production of low levels of infectious virus, which can rekindle infection when ART is stopped. Further understanding of the reservoir will be needed to clarify the mechanism(s) by which provirus expression is controlled in the clones of cells that constitute the reservoir.

scholarly journals Intensifying Antiretroviral Therapy With Raltegravir and Maraviroc During Early Human Immunodeficiency Virus (HIV) Infection Does Not Accelerate HIV Reservoir Reduction

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Mario Ostrowski ◽  
Erika Benko ◽  
Feng Yun Yue ◽  
Connie J. Kim ◽  
Sanja Huibner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Replication Competent Virus ◽  
Proviral Dna ◽  
Significant Difference ◽  
Immunodeficiency Virus ◽  
Dna 2

Abstract Background.  Persistent human immunodeficiency virus (HIV) within the CD4+ T-cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication. Methods.  A prospective, randomized, double-blinded, placebo-controlled pilot trial enrolled 32 participants with documented early (<6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4+ T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection. Results.  Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was −1.03 log DNA copies/106 CD4+ T cells versus −.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4+ T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent. Conclusions.  Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir.

scholarly journals Intragenic proviral elements support transcription of defective HIV-1 proviruses

2021 ◽  
Author(s):  
Jeffrey Kuniholm ◽  
Elise Armstrong ◽  
Brandy Bernabe ◽  
Carolyn Coote ◽  
Anna Berenson ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Treatment Interruption ◽  
Regulatory Elements ◽  
Host Cells ◽  
People Living With Hiv ◽  
Latently Infected ◽  
Infected Cells ◽  
Living With Hiv ◽  
Hiv 1

ABSTRACTHIV-establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription digital drop PCR identified Env and Nef transcripts which lacked 5’ untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5’UTR-deficient Env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5’ rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH.Author SummaryPeople living with HIV establish a persistent reservoir which includes latently infected cells that fuel viral rebound upon treatment interruption. However, the majority of HIV-1 genomes in these persistently infected cells are defective. Whether these defective HIV genomes are expressed and whether they contribute to HIV associated diseases including accelerated aging, neurodegenerative symptoms, and cardiovascular diseases are still outstanding questions. In this paper, we demonstrate that acute infection of macrophages and resting T cells is biased towards generating defective viruses which are expressed by DNA regulatory elements in the HIV genome. These studies describe an alternative mechanism for chronic expression of HIV genomes.

scholarly journals SMAC Mimetic Plus Triple-Combination Bispecific HIVxCD3 Retargeting Molecules in SHIV.C.CH505-Infected, Antiretroviral Therapy-Suppressed Rhesus Macaques

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Amir Dashti ◽  
Chevaughn Waller ◽  
Maud Mavigner ◽  
Nils Schoof ◽  
Katharine J. Bar ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Viral Reservoir ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
The Impact ◽  
Hiv 1

ABSTRACT The “shock-and-kill” human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-κB pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence. Rhesus macaques (RMs) (n = 13) were infected with simian/human immunodeficiency virus SHIV.C.CH505.375H.dCT, and triple antiretroviral therapy (ART) was initiated after 16 weeks. After 42 weeks of ART, 8 RMs received a cocktail of 3 HIVxCD3 DART molecules having human A32, 7B2, or PGT145 anti-HIV-1 envelope (Env) specificities paired with a human anti-CD3 specificity that is rhesus cross-reactive. The remaining 5 ART-suppressed RMs served as controls. For 10 weeks, a DART molecule cocktail was administered weekly (each molecule at 1 mg/kg of body weight), followed 2 days later by AZD5582 (0.1 mg/kg). DART molecule serum concentrations were well above those considered adequate for redirected killing activity against Env-expressing target cells but began to decline after 3 to 6 weekly doses, coincident with the development of antidrug antibodies (ADAs) against each of the DART molecules. The combination of AZD5582 and the DART molecule cocktail did not increase on-ART viremia or cell-associated SHIV RNA in CD4+ T cells and did not reduce the viral reservoir size in animals on ART. The lack of latency reversal in the model used in this study may be related to low pre-ART viral loads (median, <105 copies/ml) and low preintervention reservoir sizes (median, <102 SHIV DNA copies/million blood CD4+ T cells). Future studies to assess the efficacy of Env-targeting DART molecules or other clearance agents to reduce viral reservoirs after latency reversal may be more suited to models that better minimize immunogenicity and have a greater viral burden. IMPORTANCE The most significant barrier to an HIV-1 cure is the existence of the latently infected viral reservoir that gives rise to rebound viremia upon cessation of ART. Here, we tested a novel combination approach of latency reversal with AZD5582 and clearance with bispecific HIVxCD3 DART molecules in SHIV.C.CH505-infected, ART-suppressed rhesus macaques. We demonstrate that the DART molecules were not capable of clearing infected cells in vivo, attributed to the lack of quantifiable latency reversal in this model with low levels of persistent SHIV DNA prior to intervention as well as DART molecule immunogenicity.

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