Innate lymphoid cell dysfunction during long-term suppressive antiretroviral therapy in an African cohort

Abstract Background Innate lymphoid cells (ILC) are lymphoid lineage innate immune cells that do not mount antigen-specific responses due to their lack of B and T-cell receptors. ILCs are predominantly found at mucosal surfaces, as gatekeepers against invading infectious agents through rapid secretion of immune regulatory cytokines. HIV associated destruction of mucosal lymphoid tissue depletes ILCs, among other immune dysfunctions. Studies have described limited restoration of ILCs during the first three years of combined antiretroviral therapy (cART). Little is known about restoration of ILCs during long-term cART, particularly in sub-Saharan Africa which hosts increasing numbers of adults with at least a decade of cART. Results We examined phenotypes and function of ILCs from peripheral blood mononuclear cells after 12 years of suppressive cART. We report that ILC1 frequencies (T-BET + CD127 + and CD161 +) were higher in cART-treated HIV-infected relative to age-matched health HIV-negative adults; P = 0.04 whereas ILC precursors (ILCP) were comparable in the two groups (P = 0.56). Interferon gamma (IFN-γ) secretion by ILC1 was higher among cART-treated HIV-infected relative to HIV-negative adults (P = 0.03). Conclusion HIV associated alteration of ILC persisted during cART and may likely affect the quality of host innate and adaptive immune responses during long-term cART.

Download Full-text

Monocyte Dysfunction, Activation, and Inflammation After Long-Term Antiretroviral Therapy in an African Cohort

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz320 ◽

2019 ◽

Vol 220 (9) ◽

pp. 1414-1419 ◽

Cited By ~ 7

Author(s):

Rose Nabatanzi ◽

Lois Bayigga ◽

Stephen Cose ◽

Sarah Rowland Jones ◽

Moses Joloba ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Viral Suppression ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Fatty Acid Binding ◽

Sustained Viral Suppression ◽

Immunodeficiency Virus ◽

And Function ◽

Hiv Negative

Abstract Background Monocyte dysfunction may persist during antiretroviral therapy (ART). Methods Frozen peripheral blood mononuclear cells of 30 human immunodeficiency virus (HIV)-infected ART-treated adults with sustained viral suppression and CD4 counts ≥500 cells/µL were consecutively analyzed for monocyte phenotypes and function. Results Nonclassical monocytes (CD14+, CD16++), interleukin (IL)-1β production, and expression of CD40 and CD86 were lower among ART-treated HIV-infected adults relative to age-matched HIV-negative adults (P = .01, P = .01, and P = .02, respectively). Intestinal fatty acid-binding protein, IL6, and soluble CD14 were higher among HIV-infected adults relative to HIV-negative adults (P = .0002, P = .04, and P = .0017, respectively). Conclusions Further investigation is required to understand drivers of persistent monocyte activation and dysfunction.

Download Full-text

Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study

PLoS Medicine ◽

10.1371/journal.pmed.1001542 ◽

2013 ◽

Vol 10 (10) ◽

pp. e1001542 ◽

Cited By ~ 48

Author(s):

Marie-Quitterie Picat ◽

Joanna Lewis ◽

Victor Musiime ◽

Andrew Prendergast ◽

Kusum Nathoo ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Sub Saharan Africa ◽

Sub Saharan ◽

Modelling Study

Download Full-text

Intact HIV Proviruses Persist in Children Seven to Nine Years after Initiation of Antiretroviral Therapy in the First Year of Life

Journal of Virology ◽

10.1128/jvi.01519-19 ◽

2019 ◽

Vol 94 (4) ◽

Cited By ~ 2

Author(s):

Mary Grace Katusiime ◽

Elias K. Halvas ◽

Imogen Wright ◽

Kevin Joseph ◽

Michael J. Bale ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Early Treatment ◽

Mononuclear Cells ◽

Cell Clone ◽

Acute Infection ◽

Full Length ◽

Sub Saharan Africa ◽

Splice Donor Site ◽

Subtype B

ABSTRACT In adults starting antiretroviral therapy (ART) during acute infection, 2% of proviruses that persist on ART are genetically intact by sequence analysis. In contrast, a recent report in children treated early failed to detect sequence-intact proviruses. In another cohort of children treated early, we sought to detect and characterize proviral sequences after 6 to 9 years on suppressive ART. Peripheral blood mononuclear cells (PBMC) from perinatally infected children from the Children with HIV Early antiRetroviral (CHER) study were analyzed. Nearly full-length proviral amplification and sequencing (NFL-PAS) were performed at one time point after 6 to 9 years on ART. Amplicons with large internal deletions were excluded (<9 kb). All amplicons of ≥9 kb were sequenced and analyzed through a bioinformatic pipeline to detect indels, frameshifts, or hypermutations that would render them defective. In eight children who started ART at a median age of 5.4 months (range, 2.0 to 11.1 months), 733 single NFL-PAS amplicons were generated. Of these, 534 (72.9%) had large internal deletions, 174 (23.7%) had hypermutations, 15 (1.4%) had small internal deletions, 3 (1.0%) had deletions in the packaging signal/major splice donor site, and 7 (1.0%) were sequence intact. These 7 intact sequences were from three children who initiated ART after 2.3 months of age, one of whom had two identical intact sequences, suggestive of a cell clone harboring a replication-competent provirus. No intact proviruses were detected in four children who initiated ART before 2.3 months of age. Rare, intact proviruses can be detected in children who initiate ART after 2.3 months of age and are probably, as in adults, maintained by clonal expansion of cells infected before ART initiation. IMPORTANCE There are limited data about the proviral landscape in children exhibiting long-term suppression after early treatment, particularly in Sub-Saharan Africa where HIV-1 subtype C predominates. Investigating the sequence-intact reservoir could provide insight on the mechanisms by which intact proviruses persist and inform ongoing cure efforts. Through nearly full-length proviral amplification and sequencing (NFL-PAS), we generated 733 NFL-PAS amplicons from eight children. We showed that rare, genetically intact proviruses could be detected in children who initiated ART after 2.3 months of age. The frequency of intact proviruses was lower (P < 0.05) than that reported for HIV subtype B-infected adults treated during early HIV infection. We show that cells harboring genetically intact HIV proviruses are rare in children exhibiting long-term suppression after early treatment and may require the processing of a large number of cells to assess reservoir size. This points to the need for efficient methods to accurately quantify latent reservoirs, particularly in pediatric studies where sample availability is limited.

Download Full-text

Retrovirus-mediated gene transduction into canine peripheral blood repopulating cells

Blood ◽

10.1182/blood.v83.6.1467.1467 ◽

1994 ◽

Vol 83 (6) ◽

pp. 1467-1473 ◽

Cited By ~ 51

Author(s):

HP Kiem ◽

B Darovsky ◽

C von Kalle ◽

S Goehle ◽

D Stewart ◽

...

Keyword(s):

Progenitor Cells ◽

Mhc Class Ii ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Peripheral Blood Lymphocytes ◽

Lymphoid Cells ◽

Peripheral Blood Mononuclear ◽

Hematopoietic Reconstitution ◽

Peripheral Blood Progenitor Cells

Abstract Genetically marked peripheral blood progenitor cells were used to investigate their contribution to long-term hematopoietic reconstitution after autologous marrow and peripheral blood cell transplantation. After autologous marrow harvest and cryopreservation, canine peripheral blood progenitor cells were mobilized in three dogs by treatment with recombinant canine stem cell factor for 8 days. Peripheral blood mononuclear cells were collected and enriched for major histocompatibility complex (MHC) class II antigen-positive cells by avidin-biotin immunoadsorption, thereby enriching for repopulating cells. Subsequently, the cells were cocultivated for 24 hours on irradiated vector-producing packaging cells (PA317/LN), followed by an 11-day incubation in a vector containing long-term marrow culture system. On the day of transplantation, the animals were irradiated with 9.2 Gy total body irradiation (TBI), and transduced peripheral blood cells and untransduced cryopreserved marrow cells were infused within 2 hours of TBI. All three dogs engrafted. Two dogs are long-term survivors showing intermittently G418-resistant marrow-derived colony- forming unit granulocyte-macrophage colonies at a median of 1% and 2%, respectively (range, 1% to 10%), for now up to 48 weeks after transplantation. Neo-specific sequences were detected by polymerase chain reaction in peripheral blood granulocytes for now up to 65 weeks and in peripheral blood lymphocytes for up to 75 weeks after transplantation. Peripheral blood samples of the dogs were free of helper virus and no side effects from the transduction were observed. One of the three dogs died from chronic canine distemper sclerosing encephalitis on day 84, whereas the other two dogs are alive at 15 and 17 months. Our data show successful retroviral transduction of canine peripheral blood repopulating cells. Long-term persistence of marked myeloid and lymphoid cells after transplantation suggests that peripheral blood contains repopulating cells that contribute to long- term hematopoietic reconstitution after otherwise lethal TBI.

Download Full-text

Long-term outcomes of early initiated antiretroviral therapy in sub-Saharan children: a Cameroonian cohort study (ANRS-12140 Pediacam study, 2008–2013, Cameroon)

BMC Pediatrics ◽

10.1186/s12887-021-02664-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Francis Ateba Ndongo ◽

Mathurin Cyrille Tejiokem ◽

Calixte Ida Penda ◽

Suzie Tetang Ndiang ◽

Jean-Audrey Ndongo ◽

...

Keyword(s):

Cohort Study ◽

Viral Load ◽

Antiretroviral Therapy ◽

Antiretroviral Treatment ◽

Viral Suppression ◽

Virologic Response ◽

Sub Saharan Africa ◽

Factors Associated ◽

Sub Saharan

Abstract Background In most studies, the virological response is assessed during the first two years of antiretroviral treatment initiated in HIV-infected infants. However, early initiation of antiretroviral therapy exposes infants to very long-lasting treatment. Moreover, maintaining viral suppression in children is difficult. We aimed to assess the virologic response and mortality in HIV-infected children after five years of early initiated antiretroviral treatment (ART) and identify factors associated with virologic success in Cameroon. Methods In the ANRS-12140 Pediacam cohort study, 2008–2013, Cameroon, we included all the 149 children who were still alive after two years of early ART. Virologic response was assessed after 5 years of treatment. The probability of maintaining virologic success between two and five years of ART was estimated using Kaplan-Meier curve. The immune status and mortality were also studied at five years after ART initiation. Factors associated with a viral load < 400 copies/mL in children still alive at five years of ART were studied using logistic regressions. Results The viral load after five years of early ART was suppressed in 66.8% (60.1–73.5) of the 144 children still alive and in care. Among the children with viral suppression after two years of ART, the probability of maintaining viral suppression after five years of ART was 64.0% (54.0–74.0). The only factor associated with viral suppression after five years of ART was achievement of confirmed virological success within the first two years of ART (OR = 2.7 (1.1–6.8); p = 0.033). Conclusions The probability of maintaining viral suppression between two and five years of early initiated ART which was quite low highlights the difficulty of parents to administer drugs daily to their children in sub-Saharan Africa. It also stressed the importance of initial viral suppression for achieving and maintaining virologic success in the long-term. Further studies should focus on identifying strategies that would enhance better retention in care and improved adherence to treatment within the first two years of ART early initiated in Sub-Saharan HIV-infected children.

Download Full-text

Drug-Resistant Variants That Evolve During Nonsuppressive Therapy Persist in HIV-1–Infected Peripheral Blood Mononuclear Cells After Long-Term Highly Active Antiretroviral Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/00126334-200404150-00005 ◽

2004 ◽

Vol 35 (5) ◽

pp. 473-483 ◽

Cited By ~ 40

Author(s):

Chris Verhofstede ◽

Ann Noë ◽

Els Demecheleer ◽

Nancy De Cabooter ◽

Filip Van Wanzeele ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Peripheral Blood Mononuclear Cells ◽

Highly Active Antiretroviral Therapy ◽

Mononuclear Cells ◽

Drug Resistant ◽

Peripheral Blood Mononuclear ◽

Highly Active ◽

Blood Mononuclear Cells ◽

Hiv 1

Download Full-text

Retrovirus-mediated gene transduction into canine peripheral blood repopulating cells

Blood ◽

10.1182/blood.v83.6.1467.bloodjournal8361467 ◽

1994 ◽

Vol 83 (6) ◽

pp. 1467-1473 ◽

Cited By ~ 1

Author(s):

HP Kiem ◽

B Darovsky ◽

C von Kalle ◽

S Goehle ◽

D Stewart ◽

...

Keyword(s):

Progenitor Cells ◽

Mhc Class Ii ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Peripheral Blood Lymphocytes ◽

Lymphoid Cells ◽

Peripheral Blood Mononuclear ◽

Hematopoietic Reconstitution ◽

Peripheral Blood Progenitor Cells

Genetically marked peripheral blood progenitor cells were used to investigate their contribution to long-term hematopoietic reconstitution after autologous marrow and peripheral blood cell transplantation. After autologous marrow harvest and cryopreservation, canine peripheral blood progenitor cells were mobilized in three dogs by treatment with recombinant canine stem cell factor for 8 days. Peripheral blood mononuclear cells were collected and enriched for major histocompatibility complex (MHC) class II antigen-positive cells by avidin-biotin immunoadsorption, thereby enriching for repopulating cells. Subsequently, the cells were cocultivated for 24 hours on irradiated vector-producing packaging cells (PA317/LN), followed by an 11-day incubation in a vector containing long-term marrow culture system. On the day of transplantation, the animals were irradiated with 9.2 Gy total body irradiation (TBI), and transduced peripheral blood cells and untransduced cryopreserved marrow cells were infused within 2 hours of TBI. All three dogs engrafted. Two dogs are long-term survivors showing intermittently G418-resistant marrow-derived colony- forming unit granulocyte-macrophage colonies at a median of 1% and 2%, respectively (range, 1% to 10%), for now up to 48 weeks after transplantation. Neo-specific sequences were detected by polymerase chain reaction in peripheral blood granulocytes for now up to 65 weeks and in peripheral blood lymphocytes for up to 75 weeks after transplantation. Peripheral blood samples of the dogs were free of helper virus and no side effects from the transduction were observed. One of the three dogs died from chronic canine distemper sclerosing encephalitis on day 84, whereas the other two dogs are alive at 15 and 17 months. Our data show successful retroviral transduction of canine peripheral blood repopulating cells. Long-term persistence of marked myeloid and lymphoid cells after transplantation suggests that peripheral blood contains repopulating cells that contribute to long- term hematopoietic reconstitution after otherwise lethal TBI.

Download Full-text