|
1
|
Kamvuma K, Hamooya BM, Chiyenu KOR, Ademola YU, Mudenda S, Machiko A, Masenga SK, Munsaka SM. Sex differences in the risk profiles for anemia in people living with HIV, A cross sectional study. PLoS One 2025; 20:e0319611. [PMID: 40063574 PMCID: PMC11892841 DOI: 10.1371/journal.pone.0319611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 02/04/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND Anemia in people living with HIV (PLWH) significantly impacts quality of life and health outcomes. This study aimed to determine sex differences in factors associated with anemia in PLWH at Livingstone University Teaching Hospital, Zambia. METHODS This cross-sectional study involved 631 PLWH aged 18 years or older who had been on combinational ART for at least 6 months. Data was collected via standardized questionnaires and medical records. Anemia was defined as haemoglobin levels < 13 g/dL for men and < 12 g/dL for women, based on WHO criteria. Logistic regression models assessed the associated factors, stratified by sex. RESULTS Participants had a median age of 44 years, with a female preponderance of 64.2%. The overall prevalence of anemia was 36%, significantly higher in females (41.1%) compared to males (27.2%) (p < 0.001). In females, waist circumference (AOR = 0.97, 95% CI: 0.95-0.99, P = 0.018), albumin levels (AOR = 0.96, 95% CI: 0.92-0.99, P = 0.047), NNRTI regimens (AOR = 2.78, 95% CI: 1.34-5.78, P = 0.006), microcytosis (AOR = 3.18, 95% CI: 1.26-8.03, P = 0.014), and hypertension (OR = 0.34, 95% CI: 0.13-0.87, P = 0.024) were linked to anemia in adjusted analysis but these associations were abrogated by male sex. CONCLUSIONS We found a 36% prevalence of anemia among PLWH, with a higher prevalence in females (41%) compared to males (27%), including severe forms of anemia. Among females, anemia was linked to lower waist circumference, lower albumin levels, NNRTI regimens, microcytosis, and blood pressure but not males. Further studies are warranted.
Collapse
Affiliation(s)
- Kingsley Kamvuma
- Department of Pathology and Microbiology, HAND Research Group, School of Medicine and Health Sciences, Mulungush University, Livingstone Campus, Livingstone, Zambia
- Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia
| | - Benson M. Hamooya
- Department of Public Health, HAND Research Group, School of Medicine and Health Sciences, Mulungush University, Livingstone Campus, Livingstone, Zambia
| | - Kaseya O. R. Chiyenu
- Department of Internal Medicine, Livingsotne University Teaching Hospital, Livingstone, Zambia
| | - Yusuf Uthman Ademola
- Department of Pathology and Microbiology, HAND Research Group, School of Medicine and Health Sciences, Mulungush University, Livingstone Campus, Livingstone, Zambia
| | - Steward Mudenda
- Department of Pharmacy, School of Health Sciences, University of Zambia, Lusaka, Zambia
| | - Alfred Machiko
- Department of Basic Science, School Medicine, Cobberbelt Unversity, Ndola, Zambia
| | - Sepiso K. Masenga
- Department of Pathology and Microbiology, HAND Research Group, School of Medicine and Health Sciences, Mulungush University, Livingstone Campus, Livingstone, Zambia
| | - Sody M. Munsaka
- Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia
| |
Collapse
|
|
2
|
Kamvuma K, Hamooya BM, Munsaka S, Masenga SK, Kirabo A. Mechanisms and Cardiorenal Complications of Chronic Anemia in People with HIV. Viruses 2024; 16:542. [PMID: 38675885 PMCID: PMC11053456 DOI: 10.3390/v16040542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/26/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Chronic anemia is more prevalent in people living with HIV (PLWH) compared to the general population. The mechanisms that drive chronic anemia in HIV are multifaceted and include functional impairment of hematopoietic stem cells, dysregulation of erythropoietin production, and persistent immune activation. Chronic inflammation from HIV infection adversely affects erythropoiesis, erythrocyte lifespan, and erythropoietin response, leading to a heightened risk of co-infections such as tuberculosis, persistent severe anemia, and increased mortality. Additionally, chronic anemia exacerbates the progression of HIV-associated nephrotoxicity and contributes to cardiovascular risk through immune activation and inflammation. This review highlights the cardinal role of chronic inflammation as a link connecting persistent anemia and cardiovascular complications in PLWH, emphasizing the need for a universal understanding of these interconnected pathways for targeted interventions.
Collapse
Affiliation(s)
- Kingsley Kamvuma
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Livingstone 10101, Zambia; (K.K.); (B.M.H.)
| | - Benson M. Hamooya
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Livingstone 10101, Zambia; (K.K.); (B.M.H.)
| | - Sody Munsaka
- Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka P.O Box 50110, Zambia;
| | - Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Livingstone 10101, Zambia; (K.K.); (B.M.H.)
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Annet Kirabo
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| |
Collapse
|
|
3
|
Wang X, Chen M, Ma S, Ding Y, Zhou C, Yuan Y. HIV-1 Tat Protein-Mediated Inflammatory Response Inhibits the Erythroid Hematopoietic Support Function of Bone Marrow Mesenchymal Stem Cells. AIDS Res Hum Retroviruses 2022; 38:753-763. [PMID: 35972747 DOI: 10.1089/aid.2022.0011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Although combination antiretroviral therapy is widely used to treat HIV-1 infection, anemia affects the health and quality of life in a large number of these patients. The proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs), as important support cells in the hematopoietic microenvironment, can be affected by HIV-1 Tat protein. In this study, we explored the mechanism underlying the effect of Tat protein on the hematopoietic support function of BMSCs in erythroid commitment. BMSCs were treated with Tat protein or transfected with Tat mRNA and cocultured with hematopoietic stem cells (HSCs) to detect the number of erythroid colony-forming units (CFUs) and the proportion of mature red blood cells from HSCs. Subsequently, the expression level of a series of erythroid hematopoietic support factors and inflammatory factors in BMSCs after Tat treatment were analyzed. Then, the activation effect of Tat on the mitogen-activated protein kinase/nuclear factor kappa-B (MAPK/NF-κB) pathway, which is an important inflammatory response signaling pathway, was evaluated. The results showed that the number of erythroid CFUs and the production of mature red blood cells supported by BMSCs treated with Tat protein were significantly reduced and the expression of a series of erythroid supporting factors of BMSCs were significantly decreased by Tat protein. Tat-treated BMSCs highly express a variety of inflammatory mediators. Moreover, the expression of P38, p-p38, ERK1/2, p-ERK1/2, JNK1/2, p-JNK1/2, NF-κB, and p-NF-κB was significantly upregulated by Tat protein. In conclusion, Tat protein induces the inflammatory response of BMSCs by activating the MAPK/NF-κB pathway to inhibit the erythroid hematopoietic support function of BMSCs.
Collapse
Affiliation(s)
- Xiaoli Wang
- Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Meijuan Chen
- Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Shinan Ma
- Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yan Ding
- Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Chunfang Zhou
- Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China.,Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yahong Yuan
- Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| |
Collapse
|
|
4
|
Ayanaw MA, Yabeyu AB, Lenjiso G, Kifle ZD. Prevalence and predictors of thrombocytopenia among HAART naive HIV positive patients at Ambo University Referral Hospital. CLINICAL EPIDEMIOLOGY AND GLOBAL HEALTH 2022. [DOI: 10.1016/j.cegh.2022.101049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
|
|
5
|
Valverde-Villegas JM, Naranjo-Gomez M, Durand M, Rutagwera D, Bedin AS, Kankasa C, Debiesse S, Nagot N, Tuaillon E, Van de Perre P, Molès JP. The CD133 + Stem/Progenitor-Like Cell Subset Is Increased in Human Milk and Peripheral Blood of HIV-Positive Women. Front Cell Infect Microbiol 2020; 10:546189. [PMID: 33102251 PMCID: PMC7546783 DOI: 10.3389/fcimb.2020.546189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022] Open
Abstract
Human milk is a significant source of different CD133+ and/or CD34+ stem/progenitor-like cell subsets in healthy women but their cell distribution and percentages in this compartment of HIV-positive women have not been explored. To date, a decrease of CD34+ hematopoietic stem and progenitor cell frequencies in peripheral blood and bone marrow of HIV-positive patients has been reported. Herein, human milk and peripheral blood samples were collected between day 2–15 post-partum from HIV-positive and HIV-negative women, and cells were stained with stem cell markers and analyzed by flow cytometry. We report that the median percentage of CD45+/highCD34−CD133+ cell subset from milk and blood was significantly higher in HIV-positive than in HIV-negative women. The percentage of CD45dimCD34−CD133+ cell subset from blood was significantly higher in HIV-positive than HIV-negative women. Moreover, percentages of CD45dimCD34+, CD45dimCD34+CD133−, and CD45+highCD34+CD133− cell subsets from blood were significantly lower in HIV-positive than HIV-negative women. The CD133+ stem/progenitor-like cell subsets are increased in early human milk and blood of HIV-positive women and are differentially distributed to CD34+ cell subset frequencies which are decreased in blood.
Collapse
Affiliation(s)
- Jacqueline María Valverde-Villegas
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - Mar Naranjo-Gomez
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Mélusine Durand
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - David Rutagwera
- Department of Paediatrics and Child Health, University Teaching Hospital, School of Medicine University of Zambia, Lusaka, Zambia
| | - Anne-Sophie Bedin
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - Chipepo Kankasa
- Department of Paediatrics and Child Health, University Teaching Hospital, School of Medicine University of Zambia, Lusaka, Zambia
| | - Ségolène Debiesse
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - Nicolas Nagot
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, Montpellier, France
| | - Edouard Tuaillon
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, Montpellier, France
| | - Philippe Van de Perre
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, Montpellier, France
| | - Jean-Pierre Molès
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| |
Collapse
|
|
6
|
Shi X, Sims MD, Hanna MM, Xie M, Gulick PG, Zheng YH, Basson MD, Zhang P. Neutropenia during HIV infection: adverse consequences and remedies. Int Rev Immunol 2014; 33:511-536. [PMID: 24654626 PMCID: PMC4873957 DOI: 10.3109/08830185.2014.893301] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2014] [Indexed: 12/19/2022]
Abstract
Neutropenia frequently occurs in patients with Human immunodeficiency virus (HIV) infection. Causes for neutropenia during HIV infection are multifactoral, including the viral toxicity to hematopoietic tissue, the use of myelotoxic agents for treatment, complication with secondary infections and malignancies, as well as the patient's association with confounding factors which impair myelopoiesis. An increased prevalence and severity of neutropenia is commonly seen in advanced stages of HIV disease. Decline of neutrophil phagocytic defense in combination with the failure of adaptive immunity renders the host highly susceptible to developing fatal secondary infections. Neutropenia and myelosuppression also restrict the use of many antimicrobial agents for treatment of infections caused by HIV and opportunistic pathogens. In recent years, HIV infection has increasingly become a chronic disease because of progress in antiretroviral therapy (ART). Prevention and treatment of severe neutropenia becomes critical for improving the survival of HIV-infected patients.
Collapse
Affiliation(s)
- Xin Shi
- Department of Surgery, Beaumont Health System-Royal Oak, Royal Oak, MI, USA
| | - Matthew D Sims
- Department of Infectious Disease, Beaumont Health System-Royal Oak, Royal Oak, MI, USA
| | - Michel M Hanna
- Department of Infectious Disease, Beaumont Health System - Troy, Troy, MI, USA
| | - Ming Xie
- Department of Pathology, Beaumont Health System - Troy, Troy, MI, USA
| | - Peter G Gulick
- Department of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Yong-Hui Zheng
- Department of Microbiology and Molecular Genetics, College of Human Medicine
| | - Marc D Basson
- Department of Surgery, Beaumont Health System-Royal Oak, Royal Oak, MI, USA
| | - Ping Zhang
- Department of Surgery, Beaumont Health System-Royal Oak, Royal Oak, MI, USA
| |
Collapse
|
|
7
|
Wondimeneh Y, Muluye D, Ferede G. Prevalence and associated factors of thrombocytopenia among HAART-naive HIV-positive patients at Gondar University Hospital, northwest Ethiopia. BMC Res Notes 2014; 7:5. [PMID: 24387326 PMCID: PMC3916076 DOI: 10.1186/1756-0500-7-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 01/02/2014] [Indexed: 12/17/2022] Open
Abstract
Background Hematological abnormalities are common in HIV positive patients. Of these, thrombocytopenia is a known complication which has been associated with progression of disease. However, its magnitude and associated factors in HAART naive HIV positive patients is not known in Ethiopia. Therefore, the aim of this study was to determine the prevalence and associated factors of thrombocytopenia in HAART naïve HIV positive patients. Methods A retrospective study was carried out among HAART naive HIV positive patients at Gondar University Hospital, Northwest Ethiopia, from September 2011 through August 2012. Socio-demographic variables and immunohematological (platelets and CD4+ T cells) values were carefully reviewed from medical records. Associated factors and outcomes were assessed using logistic regression. Results A total of 390 HAART naive HIV positive patients with a mean age of 33.65 years and a range of 18–70 years were reviewed. The overall prevalence of thrombocytopenia was 23(5.9%). The mean CD4 count was 288 ± 188.2 cells/μL. HIV patients whose age ≥ 50 years old were 2.5 times more likely to have thrombocytopenia and those patients whose CD4 count < 350 were 2.6 times more likely to have thrombocytopenia than HIV patients whose CD4 count ≥500. However, CD4 count was not statistically associated with prevalence of thrombocytopenia (P > 0.05). Conclusion As CD4 counts of HIV patients decreasing, they have more likely to have thrombocytopenia. Therefore, early diagnosis and treatment of thrombocytopenia in these patients are necessary.
Collapse
Affiliation(s)
| | | | - Getachew Ferede
- School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, P,O, Box 196, Gondar, Ethiopia.
| |
Collapse
|
|
8
|
Gibellini D, Clò A, Morini S, Miserocchi A, Ponti C, Re MC. Effects of human immunodeficiency virus on the erythrocyte and megakaryocyte lineages. World J Virol 2013; 2:91-101. [PMID: 24175233 PMCID: PMC3785048 DOI: 10.5501/wjv.v2.i2.91] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/07/2013] [Accepted: 01/13/2013] [Indexed: 02/05/2023] Open
Abstract
Anaemia and thrombocytopenia are haematological disorders that can be detected in many human immunodeficiency virus (HIV)-positive patients during the development of HIV infection. The progressive decline of erythrocytes and platelets plays an important role both in HIV disease progression and in the clinical and therapeutic management of HIV-positive patients. HIV-dependent impairment of the megakaryocyte and erythrocyte lineages is multifactorial and particularly affects survival, proliferation and differentiation of bone marrow (BM) CD34+ haematopoietic progenitor cells, the activity of BM stromal cells and the regulation of cytokine networks. In this review, we analyse the major HIV-related mechanisms that are involved in the genesis and development of the anaemia and thrombocytopenia observed in HIV positive patients.
Collapse
|
|
9
|
Parikh N, Nonnemacher MR, Pirrone V, Block T, Mehta A, Wigdahl B. Substance abuse, HIV-1 and hepatitis. Curr HIV Res 2013; 10:557-71. [PMID: 22973853 DOI: 10.2174/157016212803306023] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 07/16/2012] [Accepted: 09/05/2012] [Indexed: 02/06/2023]
Abstract
During the course of human immunodeficiency virus type 1 (HIV-1) disease, the virus has been shown to effectively escape the immune response with the subsequent establishment of latent viral reservoirs in specific cell populations within the peripheral blood (PB) and associated lymphoid tissues, bone marrow (BM), brain, and potentially other end organs. HIV-1, along with hepatitis B and C viruses (HBV and HCV), are known to share similar routes of transmission, including intravenous drug use, blood transfusions, sexual intercourse, and perinatal exposure. Substance abuse, including the use of opioids and cocaine, is a significant risk factor for exposure to HIV-1 and the development of acquired immune deficiency syndrome, as well as HBV and HCV exposure, infection, and disease. Thus, coinfection with HIV-1 and HBV or HCV is common and may be impacted by chronic substance abuse during the course of disease. HIV- 1 impacts the natural course of HBV and HCV infection by accelerating the progression of HBV/HCV-associated liver disease toward end-stage cirrhosis and quantitative depletion of the CD4+ T-cell compartment. HBV or HCV coinfection with HIV-1 is also associated with increased mortality when compared to either infection alone. This review focuses on the impact of substance abuse and coinfection with HBV and HCV in the PB, BM, and brain on the HIV-1 pathogenic process as it relates to viral pathogenesis, disease progression, and the associated immune response during the course of this complex interplay. The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point.
Collapse
Affiliation(s)
- Nirzari Parikh
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | | | | | | | | | | |
Collapse
|
|
10
|
Pretorius E, Oberholzer HM, Smit E, Steyn E, Briedenhann S, Franz CR. Ultrastructural Changes in Platelet Aggregates of HIV Patients: A Scanning Electron Microscopy Study. Ultrastruct Pathol 2009; 32:75-9. [DOI: 10.1080/01913120802034793] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
11
|
Briand N, Lallemant M, Jourdain G, Techapalokul S, Tunthanathip P, Suphanich S, Chanpoo T, Traisathit P, McIntosh K, Le Coeur S. Haematological safety of perinatal zidovudine in pregnant HIV-1-infected women in Thailand: secondary analysis of a randomized trial. PLOS CLINICAL TRIALS 2007; 2:e11. [PMID: 17476315 PMCID: PMC1863515 DOI: 10.1371/journal.pctr.0020011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2006] [Accepted: 02/01/2007] [Indexed: 11/19/2022]
Abstract
Objectives: To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1−infected pregnant women. Design: Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis. Setting: 27 hospitals in Thailand. Participants: 1,436 HIV-infected pregnant women in PHPT-1. Intervention: Zidovudine prophylaxis initiation at 28 or 35 wk gestation. Outcome measures: Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load. Results: Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] −0.4 [−0.5 to −0.3], −423 [−703 to −142], −485 [−757 to −213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts. Conclusion: Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV. Background: Pregnant women who are infected with HIV are at high risk of passing on the virus to their unborn baby during pregnancy, labour, and breastfeeding. Around 15%–30% of babies born to HIV-positive women will themselves become infected, if the woman avoids breast-feeding but does not use any other means of preventing the virus from being passed on. However, if a drug, zidovudine (AZT), is given during pregnancy the chance of HIV being passed on to a baby drops from around 23% to around 8%. In some settings it may not be realistic to give the standard course of zidovudine, from 28 weeks of pregnancy, because of its cost and complexity. A number of trials have therefore looked at whether standard-course and short-course zidovudine are equivalent at reducing the risk of passing on HIV from mother to baby. One trial, the Perinatal HIV Prevention Trial-1 (PHPT-1) found that the short treatment course was substantially less effective at preventing HIV from being passed on from mother to baby. Current international guidance therefore recommends starting zidovudine at 28 weeks of pregnancy. However, zidovudine does have several side effects, including anemia; it can also cause a drop in the levels of certain types of white blood cell, and is thought to be toxic to bone marrow. The researchers who had carried out the PHPT-1 trial therefore wanted to do a subsequent analysis of data from that trial to find out whether there were any differences in these safety outcomes between standard and short course zidovudine. What the trial shows: In total 1,436 women were recruited into the trial and assigned to receive either zidovudine from 28 weeks of pregnancy until delivery (standard course; 769 women), or from 35 weeks to delivery (short course; 667). Blood tests were performed at 26, 32, and 35 weeks of pregnancy and then at delivery, and the main outcomes assessed in this secondary analysis were the hemoglobin levels (to check for anemia), and levels of white blood cells, including the levels of two particular types (neutrophils and lymphocytes). The researchers found that standard-course zidovudine resulted in a drop at 35 weeks in the levels of hemoglobin and white blood cells, relative to short-course zidovudine. However, by the time of delivery these levels had recovered and no significant differences could be observed between the two arms of the trial. Women receiving standard-course zidovudine were more likely to experience severe anemia, which although a rare event in both arms of the trial, could have serious outcomes. Strengths and limitations: The original trial from which these data were collected was a relatively large, randomized study and in which there was a low rate of loss to follow up. Although no formal sample size calculation was performed for the analyses presented here, the study probably had sufficient power to detect small differences in the outcomes assessed. A key limitation of this study is that the analyses presented here are a secondary exploration of data from the PHPT-1 trial and should therefore be seen as hypotheses to test in further studies, rather than as definitive conclusions. Contribution to the evidence: The analyses presented here add to the findings of the parent trial, PHPT-1, by providing additional data about the toxicity of zidovudine. Other trials have not clearly established whether there are differences between short- and standard-course zidovudine in terms of their toxicity. The findings support current guidelines recommending standard-course zidovudine therapy for HIV-positive pregnant women. It is also crucial that efforts are made to ensure women worldwide can get access to facilities for monitoring the status of their HIV infection, and then receive highly active antiretroviral therapy when it is needed.
Collapse
Affiliation(s)
- Nelly Briand
- Institut National d'Etudes Démographiques, Paris, France.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Stahl D, Lacroix-Desmazes S, Misra N, Karmochkine M, Kaveri SV, Costagliola D, Sibrowski W, Kazatchkine MD. Alterations of self-reactive antibody repertoires in HIV disease: An insight into the role of T cells in the selection of autoreactive B cells. Immunol Lett 2005; 99:198-208. [PMID: 15899522 DOI: 10.1016/j.imlet.2005.02.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2004] [Revised: 02/15/2005] [Accepted: 02/22/2005] [Indexed: 11/30/2022]
Abstract
Infection with human immunodeficiency virus (HIV) is characterized by a progressive depletion of CD4(+) T cells that parallels a dysfunction of the B cell compartment and a disturbed recognition of self-antigens. The relationship between T lymphocyte homeostasis and abnormalities in the selection of self-reactive B cells is not clear as yet. We have therefore compared repertoires of natural antibodies of healthy donors and of patients at various stages of HIV infection. The reactivity of IgM and IgG antibodies in plasma of healthy blood donors and of HIV-positive patients with high and low CD4(+) T cell counts was assessed by semi-quantitative immunoblotting using self-antigens extracted from normal human tissues. Repertoires of reactivites were compared between groups of individuals by means of multiparametric statistical analysis. We observed that repertoires of self-reactive IgM and IgG from HIV-seropositive patients exhibited significantly altered patterns of reactivity, as compared to those of healthy controls. Further, self-reactive repertoires of IgM and IgG of patients with high CD4(+) T cell counts differed significantly from those of patients with low CD4(+) T cell counts. A longitudinal analysis of self-reactive antibody repertoires of progressor and non-progressor patients suggested an influence of CD4(+) T cell counts on immunoglobulin reactivity toward self-antigens. These observations support the hypothesis that altered T cell/B cell interactions due to altered CD4(+) T cell help severely impact on the selection of self-reactive antibody repertoires and may contribute to the onset of pathological autoimmunity in HIV disease.
Collapse
Affiliation(s)
- Dorothea Stahl
- INSERM U430 and Université Pierre et Marie Curie, Institut des Cordeliers, Paris, France.
| | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Koka PS, Kitchen CMR, Reddy ST. Targeting c-Mpl for revival of human immunodeficiency virus type 1-induced hematopoietic inhibition when CD34+ progenitor cells are re-engrafted into a fresh stromal microenvironment in vivo. J Virol 2004; 78:11385-92. [PMID: 15452260 PMCID: PMC521839 DOI: 10.1128/jvi.78.20.11385-11392.2004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The inhibition of multilineage hematopoiesis which occurs in the severe combined immunodeficiency mouse with transplanted human fetal thymus and liver tissues (SCID-hu Thy/Liv) due to human immunodeficiency virus type 1 (HIV-1) infection is also accompanied by a severe loss of c-Mpl expression on these progenitor cells. Inhibition of colony-forming activity (CFA) of the CD34(+) progenitor cells is partially revived to about 40% of mock-infected Thy/Liv implants, following reconstitution of the CD34(+) cells that were exposed to HIV-1 infection, in a new Thy/Liv stromal microenvironment of irradiated secondary SCID-hu recipients at 3 weeks post-re-engraftment. In addition, in these reconstituted animals, the proportion of c-Mpl(+) CD34(+) cells relative to c-Mpl(-) CD34(+) cells increased by about 25%, to 35% of mock-infected implants, suggesting a reacquirement of c-Mpl phenotype by the c-Mpl(-) CD34(+) cells. These results suggest a correlation between c-Mpl expression and multilineage CFA of the human CD34(+) progenitor cells that have experienced the effects of HIV-1 infection. Treatment of the secondary-recipient animals with the c-Mpl ligand, thrombopoietin (Tpo), further increased c-Mpl expression and CFA of re-engrafted CD34(+) cells previously exposed to virus in the primary implants to about 50 to 70% over that of those re-engrafted CD34(+) cells derived from implants of untreated animals. Blocking of c-Mpl with anti-c-Mpl monoclonal antibody in vivo by injecting the SCID-hu animals resulted in the reduction or loss of CFA. Thus, inhibition, absence, or loss of c-Mpl expression as in the c-Mpl(-) CD34(+) subset of cells is the likely cause of CFA inhibition. Further, CFA of the CD34(+) cells segregates with their c-Mpl expression. Therefore, c-Mpl may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals.
Collapse
Affiliation(s)
- Prasad S Koka
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California-Los Angeles, 23-120 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1735.
| | | | | |
Collapse
|
|
14
|
Brockschnieder D, Lappe-Siefke C, Goebbels S, Boesl MR, Nave KA, Riethmacher D. Cell depletion due to diphtheria toxin fragment A after Cre-mediated recombination. Mol Cell Biol 2004; 24:7636-42. [PMID: 15314171 PMCID: PMC506983 DOI: 10.1128/mcb.24.17.7636-7642.2004] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Abnormal cell loss is the common cause of a large number of developmental and degenerative diseases. To model such diseases in transgenic animals, we have developed a line of mice that allows the efficient depletion of virtually any cell type in vivo following somatic Cre-mediated gene recombination. By introducing the diphtheria toxin fragment A (DT-A) gene as a conditional expression construct (floxed lacZ-DT-A) into the ubiquitously expressed ROSA26 locus, we produced a line of mice that would permit cell-specific activation of the toxin gene. Following Cre-mediated recombination under the control of cell-type-specific promoters, lacZ gene expression was efficiently replaced by de novo transcription of the Cre-recombined DT-A gene. We provide proof of this principle, initially for cells of the central nervous system (pyramidal neurons and oligodendrocytes), the immune system (B cells), and liver tissue (hepatocytes), that the conditional expression of DT-A is functional in vivo, resulting in the generation of novel degenerative disease models.
Collapse
|
|
15
|
Tripp A, Liu Y, Sieburg M, Montalbano J, Wrzesinski S, Feuer G. Human T-cell leukemia virus type 1 tax oncoprotein suppression of multilineage hematopoiesis of CD34+ cells in vitro. J Virol 2003; 77:12152-64. [PMID: 14581552 PMCID: PMC254283 DOI: 10.1128/jvi.77.22.12152-12164.2003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2003] [Accepted: 08/13/2003] [Indexed: 11/20/2022] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are highly related viruses that differ in disease manifestation. HTLV-1 is the etiologic agent of adult T-cell leukemia and lymphoma, an aggressive clonal malignancy of human CD4-bearing T lymphocytes. Infection with HTLV-2 has not been conclusively linked to lymphoproliferative disorders. We previously showed that human hematopoietic progenitor (CD34(+)) cells can be infected by HTLV-1 and that proviral sequences were maintained after differentiation of infected CD34(+) cells in vitro and in vivo. To investigate the role of the Tax oncoprotein of HTLV on hematopoiesis, bicistronic lentiviral vectors were constructed encoding the HTLV-1 or HTLV-2 tax genes (Tax1 and Tax2, respectively) and the green fluorescent protein marker gene. Human hematopoietic progenitor (CD34(+)) cells were infected with lentivirus vectors, and transduced cells were cultured in a semisolid medium permissive for the development of erythroid, myeloid, and primitive progenitor colonies. Tax1-transduced CD34(+) cells displayed a two- to fivefold reduction in the total number of hematopoietic clonogenic colonies that arose in vitro, in contrast to Tax2-transduced cells, which showed no perturbation of hematopoiesis. The ratio of colony types that developed from Tax1-transduced CD34(+) cells remained unaffected, suggesting that Tax1 inhibited the maturation of relatively early, uncommitted hematopoietic stem cells. Since previous reports have linked Tax1 expression with initiation of apoptosis, lentiviral vector-mediated transduction of Tax1 or Tax2 was investigated in CEM and Jurkat T-cell lines. Ectopic expression of either Tax1 or Tax2 failed to induce apoptosis in T-cell lines. These data demonstrate that Tax1 expression perturbs development and maturation of pluripotent hematopoietic progenitor cells, an activity that is not displayed by Tax2, and that the suppression of hematopoiesis is not attributable to induction of apoptosis. Since hematopoietic progenitor cells may serve as a latently infected reservoir for HTLV infection in vivo, the different abilities of HTLV-1 and -2 Tax to suppress hematopoiesis may play a role in the respective clinical outcomes after infection with HTLV-1 or -2.
Collapse
Affiliation(s)
- Adam Tripp
- Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York 13210, USA
| | | | | | | | | | | |
Collapse
|
|
16
|
Azzoni L, Papasavvas E, Chehimi J, Kostman JR, Mounzer K, Ondercin J, Perussia B, Montaner LJ. Sustained impairment of IFN-gamma secretion in suppressed HIV-infected patients despite mature NK cell recovery: evidence for a defective reconstitution of innate immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 168:5764-70. [PMID: 12023377 DOI: 10.4049/jimmunol.168.11.5764] [Citation(s) in RCA: 109] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The impairment of NK cell functions in the course of HIV infection contributes to a decreased resistance against HIV and other pathogens. We analyzed the proportion of mature and immature NK cell subsets, and measured subsets of IFN-gamma and TNF-alpha-producing NK and T cells in viremic or therapy-suppressed HIV-infected subjects, and noninfected control donors. Viremic HIV(+) individuals had significantly lower proportions of mature CD3(-)/CD161(+)/CD56(+) NK cells and of IFN-gamma-producing NK cells compared with noninfected donors, independent of CD4(+) T cell counts. HIV-infected subjects with undetectable viral load recovered mature CD3(-)/CD161(+)/CD56(+) NK cells and cytotoxicity against tumor (K562) and HSV-infected target cells to percentages comparable with those of uninfected individuals, but their NK cells remained impaired in their ability to produce IFN-gamma. In parallel to these ex vivo findings, in vitro NK cell differentiation of CD34-positive cord blood precursors in the presence of R5 or X4 HIV-1 resulted in the production of NK cells with a normal mature phenotype, but lacking the ability to produce IFN-gamma, whereas coculture of uninfected PBMC with HIV failed to affect mature NK cell properties or IFN-gamma secretion. Altogether, our findings support the hypothesis that mature NK cell phenotype may be uncoupled from some mature functions following highly active antiretroviral therapy-mediated suppression of HIV-1, and indicate that relevant innate immune functions of NK cell subsets may remain altered despite effective viral suppression following antiretroviral treatment.
Collapse
Affiliation(s)
- Livio Azzoni
- Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Nail S, Robert R, Dromer F, Marot-Leblond A, Senet JM. Susceptibilities of Cryptococcus neoformans strains to platelet binding in vivo and to the fungicidal activity of thrombin-induced platelet microbicidal proteins in vitro. Infect Immun 2001; 69:1221-5. [PMID: 11160027 PMCID: PMC98011 DOI: 10.1128/iai.69.2.1221-1225.2001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
In this study we investigated the interactions between capsular and acapsular strains of Cryptococcus neoformans and blood platelets. In vivo microscopic observation of blood samples from mice inoculated with C. neoformans yeast cells demonstrated that encapsulated and nonencapsulated yeast cells disappeared quickly from the bloodstream and that platelets were attached solely to yeast cells of the nonencapsulated strains. In vitro we observed that only the acapsular strains were susceptible to the fungicidal activity of thrombin-induced platelet microbicidal proteins.
Collapse
Affiliation(s)
- S Nail
- Groupe d'Etude des Interactions Hôte-Parasite, Laboratoire de Parasitologie-Mycologie, Faculté de Pharmacie, 49000 Angers, France
| | | | | | | | | |
Collapse
|
|
18
|
Abstract
BACKGROUND Anemia in pregnancy is a major public health problem in developing countries. In sub-Saharan Africa, such anemia is generally accepted as resulting from nutritional deficiencies, particularly iron deficiency. OBJECTIVE We comprehensively assessed the full spectrum of nutritional and nonnutritional factors associated with pregnancy anemia. DESIGN Iron, folate, vitamin B-12, and vitamin A were measured in serum in a cross-sectional study of 150 pregnant women in Blantyre, Malawi. Bone marrow aspirates were evaluated, peripheral blood films were examined for malaria parasites, stool and urine samples were examined for helminthic infection, and tests were done for genetic disorders and for HIV infection. C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates were measured as markers of inflammation. RESULTS Of the 150 anemic women, 23% were iron deficient with no evidence of folate, vitamin B-12, or vitamin A deficiencies; 32% were deficient in iron and one or more of the other micronutrients; 26% were not iron deficient but had evidence of one of the other micronutrient deficiencies, most often vitamin A; and 19% were not deficient in any of the micronutrients studied. CRP concentrations were notably high in 54% of the anemic women with no nutritional deficiencies and in 73.5% of the anemic women who were iron replete by bone marrow assessment. CONCLUSION The role of chronic inflammation as a possible contributing factor to anemia in pregnancy has important implications for the clinical evaluation and treatment of women.
Collapse
Affiliation(s)
- N R van den Broek
- Departments of Obstetrics and Gynaecology, College of Medicine Blantyre, Malawi.
| | | |
Collapse
|
|
19
|
Koka PS, Jamieson BD, Brooks DG, Zack JA. Human immunodeficiency virus type 1-induced hematopoietic inhibition is independent of productive infection of progenitor cells in vivo. J Virol 1999; 73:9089-97. [PMID: 10516015 PMCID: PMC112941 DOI: 10.1128/jvi.73.11.9089-9097.1999] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/1999] [Accepted: 07/14/1999] [Indexed: 11/20/2022] Open
Abstract
Human immunodeficiency virus (HIV)-infected individuals exhibit a variety of hematopoietic dysfunctions. The SCID-hu mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues) can be used to model the loss of human hematopoietic precursor cell function following HIV infection and has a distinct advantage in that data can be obtained in the absence of confounding factors often seen in infected humans. In this study, we establish that HIV type 1 (HIV-1) bearing a reporter gene inserted into the viral vpr gene is highly aggressive in depleting human myeloid and erythroid colony-forming precursor activity in vivo. Human CD34(+) progenitor cells can be efficiently recovered from infected implants yet do not express the viral reporter gene, despite severe functional defects. Our results indicate that HIV-1 infection alone leads to hematopoietic inhibition in vivo; however, this effect is due to indirect mechanisms rather than to direct infection of CD34(+) cells in vivo.
Collapse
Affiliation(s)
- P S Koka
- Division of Hematology, Department of Medicine, Jonsson Comprehensive Cancer Center, UCLA AIDS Institute, UCLA School of Medicine, Los Angeles, California 90095, USA
| | | | | | | |
Collapse
|
|
20
|
Affiliation(s)
- H van den Berg
- Department of Pediatric Oncology, Emma Children's Hospital, University of Amsterdam, The Netherlands
| | | | | |
Collapse
|
|
21
|
Koka PS, Fraser JK, Bryson Y, Bristol GC, Aldrovandi GM, Daar ES, Zack JA. Human immunodeficiency virus inhibits multilineage hematopoiesis in vivo. J Virol 1998; 72:5121-7. [PMID: 9573283 PMCID: PMC110080 DOI: 10.1128/jvi.72.6.5121-5127.1998] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4(+) lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.
Collapse
Affiliation(s)
- P S Koka
- Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Lee B, Doranz BJ, Ratajczak MZ, Doms RW. An intricate Web: chemokine receptors, HIV-1 and hematopoiesis. Stem Cells 1998; 16:79-88. [PMID: 9554031 DOI: 10.1002/stem.160079] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cellular infection by the human immunodeficiency virus type 1 (HIV-1) requires interaction of the viral envelope protein with CD4 and at least one additional cell surface molecule, termed a "cofactor" or "coreceptor." Recent discoveries have determined that macrophage-tropic strains of HIV-1 which are largely responsible for sexual transmission require the beta-chemokine receptor CCR5 in addition to CD4, while the T cell tropic viruses that emerge later after infection use the alpha-chemokine receptor CXCR4. Thus, both CD4 and the appropriate chemokine receptor must be expressed on the cell surface in order for HIV-1 to enter the cell and establish an infection. The in vivo importance of CCR5 for HIV-1 is demonstrated by the finding that individuals homozygous for a 32 bp deletion (delta 32) in the CCR5 gene that renders them effectively CCR5-negative are highly resistant to virus infection. In this review, the structure-function correlates of the chemokine receptors that serve as major coreceptors for HIV-1 and simian immunodeficiency virus entry will be reviewed. Since certain chemokines have been implicated as stem cell inhibitory factors, the biological consequences of chemokine receptor expression as it relates to HIV-1-associated hematodyspoiesis will also be discussed.
Collapse
Affiliation(s)
- B Lee
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA
| | | | | | | |
Collapse
|
|
23
|
van den Broek N. Anaemia in pregnancy in developing countries. BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY 1998; 105:385-90. [PMID: 9609262 DOI: 10.1111/j.1471-0528.1998.tb10120.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- N van den Broek
- Department of Obstetrics and Gynaecology, Medical College Malawi
| |
Collapse
|
|
24
|
Klassen MK, Lewin-Smith M, Frankel SS, Nelson AM. Pathology of human immunodeficiency virus infection: noninfectious conditions. Ann Diagn Pathol 1997; 1:57-64. [PMID: 9869826 DOI: 10.1016/s1092-9134(97)80009-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Diagnostic anatomic pathologists play a crucial role in the battle against acquired immunodeficiency syndrome (AIDS). Not only are they intimately involved in the treatment of individual patients with human immunodeficiency virus (HIV) infection, but also they make important observations that result in the expansion of the scientific understanding of its pathogenesis. Pathologists studying tissue from patients with HIV infection should be familiar with the conditions to which these patients are susceptible. Although opportunistic infections are important causes of morbidity and mortality, noninfectious conditions frequently make substantial contributions to the disease course. Patients with HIV infection may be at increased risk for neoplastic disease. They do not, however, have an increased incidence of the most common tumors affecting the general population, such as breast, colon, and prostate carcinoma. Immunodeficiency results in increased susceptibility to malignant neoplasms, both by decreased immunologic response to abnormal cells and increased susceptibility to infection by viruses. All of the malignant neoplastic diseases that are Centers for Disease Control and Prevention (CDC) AIDS indicator conditions have been shown to have an association with a virus: Kaposi sarcoma (KS) with herpes hominis virus 8 (HHV-8), malignant lymphoma with Epstein-Barr virus (EBV), and cervical carcinoma with human papilloma virus (HPV). Patients with HIV infection also can develop reactive processes that are attributable to direct effects of HIV or immune system alterations. Such conditions include salivary gland cystic lymphoepithelial lesion, lymphadenopathy, lymphocytic interstitial pneumonitis, encephalopathy, enteropathy, nephropathy, hepatic conditions, dermatologic conditions and anemia.
Collapse
Affiliation(s)
- M K Klassen
- Department of Infectious and Parasitic Disease Pathology, Armed Forces Institute of Pathology, Washington, DC, USA
| | | | | | | |
Collapse
|
|
25
|
Infection of Human Marrow Stroma by Human Immunodeficiency Virus-1 (HIV-1) Is Both Required and Sufficient for HIV-1–Induced Hematopoietic Suppression In Vitro: Demonstration by Gene Modification of Primary Human Stroma. Blood 1997. [DOI: 10.1182/blood.v90.5.1787] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractPatients with human immunodeficiency virus-1 (HIV-1) infection often present with bone marrow (BM) failure that may affect all hematopoietic lineages. It is presently unclear whether this failure reflects a direct viral impairment of the CD34+ hematopoietic progenitor cells or whether the virus affects the BM microenvironment. To study the effects of HIV-1 on the BM microenvironment, we examined the stromal cell monolayers in long-term BM culture (LTBMC), which are the in vitro equivalent of the hematopoietic microenvironment. We assessed the hematopoietic support function (HSF ) of human stromal layers by determining the cellular proliferation and colony-forming ability of hematopoietic progenitors from BM cells grown on the stromal layers. We show that the HSF is reduced by in vitro infection of the human stromal cell layer by a monocytotropic isolate of HIV-1 (JR-FL). There is no loss of HSF when the stromal cell layer is resistant to HIV-1 replication, either using murine stromal cell layers that are innately resistant to HIV-1 infection or using human stromal cells genetically modified to express a gene that inhibits HIV-1 replication (an RRE decoy). Decreased HSF was seen using either human or murine hematopoietic cells, if the stromal cells were human cells that were susceptible to HIV-1 infection. These in vitro studies implicate HIV-1 replication in the stroma as the essential component causing decreased hematopoietic cell production in HIV-1 infection.
Collapse
|
|
26
|
Kearns K, Bahner I, Bauer G, Wei SF, Valdez P, Wheeler S, Woods L, Miller R, Casciato D, Galpin J, Church J, Kohn DB. Suitability of bone marrow from HIV-1-infected donors for retrovirus-mediated gene transfer. Hum Gene Ther 1997; 8:301-11. [PMID: 9048197 DOI: 10.1089/hum.1997.8.3-301] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Bone marrow samples from 21 human immunodeficiency virus type 1 (HIV-1)-infected subjects were evaluated for their suitability for retrovirus-mediated gene transduction with anti-HIV-1 genes. The percentages of CD34+ cells that could be isolated from the mononuclear fraction of bone marrow samples were determined. Fifteen of the 21 marrow samples had normal percentages of CD34+ cells isolated by immunomagnetic methods. All seven donors with CD4 counts > 100/mm3 had normal percentages of CD34+ cells; of 14 patients with low CD4 cell counts (< 100/mm3), 5 had reduced and 9 had normal percentages of CD34+ cells. Samples of the marrow were plated in a methylcellulose colony-forming unit (CFU) assay to determine the clonogenic capacity of the progenitor cells. Overall, the marrow samples from HIV-infected donors showed a 44% reduction in CFU derived from the mononuclear cell fraction and a 75% reduction in CFU derived from the isolated CD34+ cell fraction, when compared to marrow samples from uninfected donors. Isolated CD3+ cells were transduced with retroviral vectors containing various anti-HIV-1 genes to determine their susceptibility to gene transfer. Transduction of the clonogenic CD34+ cells by retroviral vectors did not differ among marrow samples from 13 HIV-1+ donors and 9 uninfected donors. Long-term bone marrow cultures established from the transduced CD34+ cells demonstrated equivalent survival of clonogenic progenitor cells from both HIV-1-infected and uninfected marrows. Toxicity from expression of the anti-HIV-1 genes was not observed; the percentages of clonogenic progenitor cells that survived in cultures transduced by vectors carrying anti-HIV-1 genes were similar to those transduced by the control LN vectors. Stromal cells cultured from marrow samples from HIV-1-infected donors showed similar growth kinetics, hematopoietic support function, and enhancement of retrovirus-mediated transduction of CD34+ cells as seen with stromal cells cultured from uninfected marrow donors. Semi-quantitative polymerase chain reaction (PCR) was performed before and after ex vivo transduction to determine the frequency of HIV-1-containing cells in the CD34+ cell preparations. Although HIV-1+ cells were present at low levels in the mononuclear cell fractions of some of the marrow samples, the CD34+ cell preparation from only one marrow sample contained detectable HIV-1 positive cells (< 1 positive cell/100,000 by PCR) prior to transduction. None of the CD34+ cell preparations contained detectable HIV-1 after transduction. These studies demonstrate that HIV-1-infected patients are candidates for retrovirus-mediated transduction of anti-HIV-1 genes in bone marrow gene therapy clinical trials.
Collapse
Affiliation(s)
- K Kearns
- Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital Los Angeles, University of Southern California School of Medicine 90027, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Chêne G, Easterbrook PJ, Juszczak E, Yu LM, Pocock SJ, Gazzard BG. Long-term survival in patients with advanced immunodeficiency. AIDS 1997; 11:209-16. [PMID: 9030369 DOI: 10.1097/00002030-199702000-00012] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To identity prognostic factors associated with survival time in HIV-infected patients with advanced immunodeficiency. DESIGN Prospective cohort study. PARTICIPANTS A total of 1284 HIV-infected patients with serial CD4 count measurements and at least one CD4 cell count < or = 50 x 10(6)/I (CD4 < or = 50). MAIN OUTCOME MEASURE Survival from initial CD4 cell count < or = 50 x 10(6)/l. RESULTS The median survival from initial CD4 < or = 50 x 10(6)/l was 17.1 months. The risk of death increased by 2% 195% confidence interval (Cl), 1-31 for each year of age, by 10% (95% Cl, 3-16) for each 10 x 10(6)/l decrease in CD4 count, and by 14% (95% Cl, 9-18) for each 1 g/dl decrease in haemoglobin level. Compared to AIDS-free patients with CD4 < or = 50 x 10(6) cells/l, the risk of dying was 1.5-fold (95% Cl, 1.2-1.9) that of patients who had an AIDS diagnosis for fewer than 3 months prior to CD4 < or = 50, 1.8-fold for patients with an AIDS diagnosis for 4-11 months prior to CD4 < or = 50, and twice that of patients with AIDS for > or = 12 months prior to CD4 < or = 50. The risk of dying for patients whose rate of CD4 cell decline was > 40 x 10(6)/l per 6 months was 1.7-fold (95% Cl, 1.3-2.3) that of patients with an average CD4 cell loss < 40 x 10(6)/l per 6 months, after adjusting for age, haemoglobin and duration of AIDS prior to CD4 < or = 50 x 10(6) cells/l. A prognostic score was developed from the final multivariate model, based on age at CD4 < or = 50, haemoglobin at CD4 < or = 50, duration of AIDS and rate of CD4 decline prior to CD4 < or = 50. CONCLUSIONS Routinely available clinical and laboratory data including haemoglobin level, rate of CD4 decline and duration of AIDS can be readily translated into a prognostic score and then used to predict the survival experience of an HIV-infected patient with advanced immunodeficiency.
Collapse
Affiliation(s)
- G Chêne
- Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Chelsea and Wistminster Hospital, London, UK
| | | | | | | | | | | |
Collapse
|
|
28
|
Newell M, Goldstein D, Milliken S, Lewis C, Hoy J, Thomson B, Cooper D. Phase I/II trial of filgrastim (r-metHuG-CSF), CEOP chemotherapy and antiretroviral therapy in HIV-related non-Hodgkin's lymphoma. Ann Oncol 1996; 7:1029-36. [PMID: 9037361 DOI: 10.1093/oxfordjournals.annonc.a010495] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND A phase I/II trial determined the maximum tolerated dose (MTD) of CEOP for AIDS-related non-Hodgkin's lymphoma (NHL) with concurrent filgrastim and antiretroviral therapy. PATIENTS AND METHODS Fourteen AIDS-NHL patients, chemotherapy naïve and ECOG performance status < 2 received filgrastim 1.0 microgram/kg s.c. daily for 3-7 days to assess neutrophil response, followed by CEOP with filgrastim support 10 micrograms/kg s.c. daily, day 2-14, continued if the absolute neutrophil count (ANC) < 1.2 x 10(9)/l. Two CEOP dose cohorts were used: cohort 1 (5 patients) - cyclophosphamide (C) 500 mg/m2, epirubicin (E) 37.5 mg/m2, vincristine (O) 2 mg and prednisolone (P) 75 mg/m2 daily on days 1-5; cohort 2 (9 patients) - C 750 mg/m2, E 50 mg/m2, same doses of O and P. Antiretroviral therapy was maintained (zidovudine-10, ddI-3, both-1). RESULTS In cohort 1, 4/5 patients received at least 3 courses of CEOP with one complete response after five cycles and four progressions. Four have died (3-21 months after entry) with 1 alive at 40 months. Dose limiting toxicity (DLT - grade IV febrile neutropenia in cycle 1) occurred in 1 patient. In cohort 2, 5/9 completed > or = 5 cycles with 6 complete responses, 1 partial response and 2 progressions, 6 deaths and 3 alive at > 33 months. DLT (evaluable in 8 patients) occurred in two patients. Median survival for both cohorts was 17 months. Mean relative dose intensity was > 85%. CONCLUSIONS The dosages of CEOP in cohort 1 defined the MTD however, the cohort 2 doses with filgrastim and antiretroviral therapy gave an encouraging response, acceptable toxicities and merit further study.
Collapse
Affiliation(s)
- M Newell
- National Center in HIV Epidemiology and Clinical Research, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Relf MV. Xenotransplantation of baboon bone marrow cells: a historical review of the protocols as a possible treatment modality for HIV/AIDS. J Assoc Nurses AIDS Care 1996; 7:27-35. [PMID: 8906734 DOI: 10.1016/s1055-3290(96)80043-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Despite great advances and a significant understanding of HIV pathogenesis, no curative treatment modality currently exists. Since baboon bone marrow cells (BBMC) are believed to be resistant to the human immunodeficiency virus, researchers have recently transplanted BBMC into two patients with AIDS, a process known as xenotransplantation. The purpose of this paper is to provide a comparative analysis of human and baboon hematopoiesis, followed by a review of the pathophysiologic effects of the HIV on the human hematologic and immune systems. The two protocols implemented since 1994 are discussed, including an overview of the potential risks and benefits and implications for nursing practice.
Collapse
Affiliation(s)
- M V Relf
- Johns Hopkins University, Baltimore, MD, USA
| |
Collapse
|