HTLV-I Infection Research Articles

Sero-Prevalence of Bloodborne Tumor Viruses (HCV, HBV, HTLV-I and KSHV Infections) and Related Risk Factors among Prisoners in Razavi Khorasan Province, Iran, in 2008.

BackgroundPrisoners are at high risk of blood borne and sexually transmitted infections due to their high involvement in risky behaviors. In this descriptive/cross-sectional study, the prevalence, sero-prevalence, and risk factors for bloodborne tumor viruses including HTLV-I, HBV, HCV, and KSHV were evaluated among inmates of two central prisons in the northeast of Iran.MethodsBlood samples of 1114 inmates were analyzed for the presence of anti HTLV-I, KSHV, and HCV antibodies and HBsAg by ELISA. PCR tests were performed to confirm the presence of these viruses in plasma and identify the current infections.ResultsThe sero-prevalence of HCV, HBV, HTLV-I, and KSHV was 24.5%, 4.2%, 3.4%, and 3.2% and the prevalence of HCV, HBV, HTLV-I, and KSHV was 19.1%, 2.1%, 2%, and 3%, respectively. HCV infection was significantly associated with history of imprisonment, tobacco consumption, alcohol consumption, intravenous drug use, length of imprisonment, and type of crime committed. Thirty one (2.8%) prisoners had HCV-KSHV co-infection, 16 (1.5%) had HCV-HTLV-I co-infection, and 14 (1.3%) had HBV-HCV co-infection. Triple co-infection was observed in seven cases and one case had four infections concomitantly.ConclusionsThis epidemiological study indicated different rates and transmission risks for these viruses. HCV was the most contagious viral infection and HTLV-I was the weakest in the prisoners. Apart from KSHV infection which its prevalence was as twice as in the general population, the prevalence of HBV and HTLV-I in prisoners was nearly in ranges of the general population.

PF2-034 - A Case of gastrointestinal stromal tumor complicated by hypercalcemia induced by parathyroid hormone-related protein

Background: Hypercalcemia is often associated with malignant tumors. Eighty percent of cases with hypercalcemia are caused by overproduced parathyroid hormone-related protein (PTHrP) in tumor cells (humoral hypercalcemia of malignancy; HHM). HHM has hardly been in GIST. Few case reports of GIST with increased serum level of PTHrP have been reported. Case: A 73-year-old Japanese male, with a background history of hypothyroidism and gastric cancer, had underwent subtotal gastrectomy. However, follow-up examination revealed the peritoneal dissemination, definitely diagnosed as KIT-positive GIST of small intestinal origin. The patient had been treated with tyrosine kinase inhibitors; imatinib for 2 years 2 months, sunitinib for 1 year 10 months and regorafenib, successively up to progressive disease (PD). On regorafenib treatment day 14, the patient developed erythema multiforme type drug eruption. After recovery from the allergic reaction, he voluntarily participated in an industry-initiated clinical study at our hospital. Since before the study drug administration, the serum calcium level had gradually increased. To improve the hypercalcemia, elcatonin, isotonic saline, zoledronic acid and denosumab were stepwisely administered. Hence, we found the serum PTHrP level was elevated (38.9pmol/l, reference value: <1.1 pmol/l). We therefore diagnosed his illness as HHM. There was no evidence of either recurrence of the early gastric cancer or bone metastases or HTLV-I infection. After 4 months from termination of regorafenib administration, he died of malignant tumor progression. Conclusion: We report herein a rare case of HHM associated with GIST with increased serum level of PTHrP. Our intensive literature search revealed only one prior report on a similar case.

Kidney Paired Donation Protocol for Participating Donors 2014.

Kidney Paired Donation Protocol for Participating Donors 2014.

Deciphering the molecular basis of arsenic/interferon-alpha induced eradication of leukemia initiating cells in adult T cell leukemia

Adult T-cell leukemia (ATL) is a severe, chemotherapy-resistant malignancy caused by chronic HTLV-I infection and associated with dismal long-term prognosis. The HTLV-I oncoprotein Tax initiates ATL in transgenic mice. We have previously shown that arsenic trioxide and interferon-α (IFN) combination, known to trigger proteasome mediated Tax proteolysis and apoptosis in HTLV-I transformed or fresh ATL cells, cures Tax-driven ATL in mice. Unexpectedly, this combination therapy of primary donor mice abrogated leukemia initiating cells (LIC) engraftment into untreated secondary recipients, whereas the primary tumor bulk still grew in the primary hosts, only to ultimately abate later on. This loss of initial transplantability required proteasomal function. Furthermore, these preclinical results led to very promising improvement in ATL patients when arsenic was added to zidovudine and IFN. To decipher the molecular basis of LIC eradication in the murine ATL Tax transgenic model, primary ATL donor mice were treated with arsenic/IFN for 3 days starting on day 18 post-leukemic cells inoculation and sacrificed at day 21. Spleen derived ATL cells were intraperitoneally injected into secondary recipient SCID mice that were left untreated and were sacrificed on a weekly basis. Whereas, secondary mice derived from untreated primary succumbed from ATL between 3 and 4 weeks after transplantation, we observed an unprecedented biphasic growth in secondary mice transplanted from arsenic/interferon treated primary mice. Indeed, the tumor increased progressively until week 5 with organ infiltration and leukocytosis, followed by a spontaneous and dramatic tumor regression for 2 weeks before a second phase of tumor growth that culminates in death from ATL at around 9-10 weeks. ATL cells derived from the initial phase of growth (week 4) were healthy, TUNEL negative and showed a normal capacity in inducing ATL in tertiary hosts. Strikingly, ATL cells derived from the second phase of growth (weeks 7 to 9) showed a progressive increase in p53 expression and TUNEL positivity reaching more than 50% at week 9, and lost their capacity to induce ATL in tertiary hosts. Finally, gene expression profile revealed an arsenic/interferon signature that was similar at Week 4 and Week 8 as well as a specific signature at Week 8 concomitant with the loss of LIC activity. These results represent a unique and novel model of studying treatment-induced LIC eradication.

Paraparesia espástica tropical autóctona en la Comunidad de Madrid. Experiencia en el cribado del virus linfotrópico de células T humanas tipo I

We have recently documented a case of tropical spastic paraparesis by HTLV-I in a Spanish patient. HTLV-I infection is rare in Europe, and hardly ever is accompanied by symptoms, but if it does it could trigger a major health issue. This case is presented here, as well as a discussion on the situations in which HTLV-I detection is justified. An analysis was made of the HTLV diagnostic requests at our centre during 2014-2015 (n=123). The diagnostic algorithm was: 1) Enzyme immunoassay, 2) Reverse hybridization, and 3) Proviral DNA detection by PCR. The results showed several situations of HTLV screening, emphasising those related to paraparesis (22%). Seven cases of HTLV-I infection were found: five in patients from endemic regions, one in an HIV-infected patient, and the case of TSP mentioned above. HTLV-I surveillance in non-endemic regions is a challenging issue, as the cost-benefit ratio is not well-established. This case report emphasises the importance of including HTLV within the differential diagnosis of insidious spastic paraparesis.

Dynamics of an infection model with two delays

In this paper, a HTLV-I infection model with two delays is considered. It is found that the dynamics of this model are determined by two threshold parameters R0 and R1, basic reproduction numbers for viral infection and for CTL response, respectively. If R0 &lt; 1, the infection-free equilibrium P0 is globally asymptotically stable. If R1 &lt; 1 &lt; R0, the asymptomatic-carrier equilibrium P1 is globally asymptotically stable. If R1 &gt; 1, there exists a unique HAM/TSP equilibrium P2. The stability of P2 is changed when the second delay τ2 varies, that is there exist stability switches for P2.

Dynamical behaviors of an HTLV-I infection model with intracellular delay and immune activation delay

This paper investigates the dynamics of an HTLV-I infection model with intracellular delay and immune activation delay. The primary objective of the study is to consider the effect of the time delay on the stability of the infected equilibrium. Two sharp threshold parameters $\Re_{0}$ and $\Re_{1}$ are identified as the basic reproduction number for viral infection and for CTLs response, respectively, which determine the long time behaviors of the viral infection. In particular, our mathematical analysis reveals that a Hopf bifurcation occurs when immune activation delay passes through a critical value. Using the normal form theory and center manifold arguments, the explicit formulae which determine the stability, the direction, and the period of bifurcating periodic solutions are derived. Numerical simulations are given to support the theoretical results.

Global existence of periodic solutions in an infection model

Abstract In this paper, a HTLV-I infection model with CTL immune response is considered. Taking the immune delay as a bifurcation parameter we investigate the global existence of periodic solutions of this model which shows existence of multiple periodic solutions theoretically.

Risk of Transmission of Human T-Lymphotropic Virus Through Transplant

To the Editor: As Ramanan et al indicate in their report of the first human T-lymphtropic virus (HTLV) associated myelopathy acquired through live donor kidney transplant in the United States, prevalence of HTLV infection varies considerably in different parts of the world 1. Seroprevalence of HTLV as high as 4.4% has been reported in Central Brooklyn 2. We conducted an Institutional Review Board-approved review of serostatus of 362 potential live kidney donors that presented for evaluation to Downstate Medical Center from 1999 to 2008 and identified eight (2.2%) who were HTLV seropositive. Serology for HTLV was performed with enzyme immunoassay and Western blot (Quest Diagnostics, Madison, NJ). We also analyzed the geographic distribution of HTLV-positive deceased donors (DD) using Scientific Registry of Transplant Recipients data from 1987 to 2011. There were 176 (0.16%) HTLV-positive donors among 106 141 DDs, after excluding donors with equivocal or unknown serological results. Although the overall prevalence of HTLV seropositivity is low, HTLV-positive donors appear to cluster in certain states, as shown in Table 1. Specifically, states with the 10 highest numbers of HTLV-positive DDs account for 56.1% of all HTLV-positive DDs nationally. HTLV-positive donors were older (45.8 ± 2.3 vs. 38.6 ± 0.1, p < 0.001) and had higher rates of serpositivity for VDRL, hepatitis C virus (HCV), and hepatitis B core antibody (2.8% vs. 0.8%, 11.5% vs. 3.5%, and 11% vs. 5.4%, respectively; p < 0.01 for all three comparisons by χ2). The proportion of donors who meet criteria for high-risk behavior as defined by Centers for Disease Control and Prevention was also higher (13% vs. 8%, p = 0.03 by χ2) in the HTLV-positive group. Logistic regression analysis, however, showed only age (odds ratio [OR] [CI] per decade: 1.16 [1.05–1.22], p = 0.003) and HCV seropositivity (OR [CI]: 2.0 [1.1–3.6], p = 0.03) to be independently associated with HTLV seropositivity, suggesting that clinical predictors have limited role in identifying HTLV-infected donors. Screening serological assays do not distinguish HTLV-I from HTLV-II infections—an important distinction as the clinical relevance of HTLV-II infection is uncertain—and have low specificity. Unlike the results from SRTR data, these shortcomings are less likely to have influenced our center's results in view of additional testing performed using Western blot, and predominance of HTLV-I infection and endemicity of HTLV-associated disease previously reported in our area 2-4. Overall, the observations described above highlight the geographic heterogeneity of risk for HTLV transmission through transplantation. We suggest that Organ Procurement Organizations and transplant programs ascertain their local prevalence of HTLV infection to help guide appropriate screening of live and deceased donors. F. Tedla1,*, A. Brar1, D. John2 and N. Sumrani2 1Division of Nephrology, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY 2Division of Transplant Surgery, Department of Surgery, State University of New York Downstate Medical Center, Brooklyn, NY *Corresponding author: Fasika Tedla, fasika.tedla@downstate.edu The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Obituary for Guy de Thé

Guy de The, MD, PhD, passed away on August 7, 2014, aged 84. He had obtained his MD in Marseille, as a resident in haematology/Oncology. He then undertook a PhD, which he defended in 1967, partly in France at the Centre National de la Recherche Scientifique (CNRS) in Villejuif, and in the US, working at Duke University with J. Beard and at the National Cancer Institute with R. Bryan. He then became head of the Biological Carcinogene unit at the International Agency for Cancer Research in Lyon up to 1978. He then directed a CNRS laboratory in Lyon and, finally created the Unit of Epidemiology of Oncogenic Viruses at the Institut Pasteur in 1990. After his official retirement in 1997, he actively engaged into academic life, notably at an international level, with the Inter Academy Medical Panel. He was affiliated with the French Academy of Science, of Medicine, the American Institute for Medicine and the Chinese Academy of Preventive Medicine. He has been one of the founders and the President of the International Association for Retrovirology HTLV. Guy de The devoted his research efforts to the oncogenic viruses, particularly in developing countries that pay a high toll to these pathogens. His approaches were particularly broad, ranging from electron microscopy imaging, classic virology, immuno-virology, up to field epidemiology and even anthropology. He trained during all his life, spending multiples stays in the US (Duke, Harvard, NCI), England (Oxford), as well as in China. Early on, he had chosen viruses, especially herpes-viruses and retroviruses, as the entry point for cancer biology. A passionate advocate for research, ready to take many challenges, he initiated many projects that bridged field and laboratory work, particularly in Africa and Southern China. He was a pioneer in EBV research, prospectively demonstrating, in a very large study performed in Uganda, the key role of early EBV activation in Burkitt's lymphoma [1] (Figure 1). He also pioneered the field of EBV and nasopharyngeal carcinoma (NPC) [2]. Beside some important genetic studies [3], he demonstrated, through large collaboration with Chinese colleagues, that EBV reactivation could be used to predict the development of NPC [4,5]. Finally, while the relationship between retroviral infections and neurodegenerative diseases are well known in animals, he was the first one to demonstrate that HTLV-I infection can drive a chronic and severe neurological condition (Tropical Spastic Paraparesis) frequent in HTLV-1 endemic areas [6,7]. Figure 1 Guy de The in Institut Pasteur Paris in the early 1990’s, showing a map of Africa where the Burkitt prospective study took place. Author of over 300 scientific publications, Guy was also a talented writer, author of many books for the general public in the context of the origin and prevention of cancer. He also organized and was the chairman of several important internationl symposium on mainly oncogenic viruses, especially EBV and HTLV-1. Guy was an enthusiastic man, always looking for novel clues linking viruses and diseases, anywhere in the world. He had close friends all over the world, notably in China, where he was one of the first French Scientists to establish effective collaborations with Chinese scholars as early as 1977. He trained numerous young researchers and always gave a chance to those who knew how to grab it. His colleagues depict him as a kind, elegant and benevolent man, interested in the discoveries and successes of others. He also had a passion for art, in which he hoped to find the same intrinsic beauties as in biological systems. His friends and family deeply miss him.

Association between HLA-DQB1 alleles and HAM/TSP patients in Khorasan Province.

HTLVI-1 is the first human retrovirus with limited endemic regions in the world. The epidemiological studies have shown that the genetic background and immune response to the virus have a significant role in HTLV-I-associated diseases. Among the genes are involved in HTLV-I infection, the role of human leukocytes antigen (HLA) have been studied in different population. In the present study we examined the association between HLA-DQB1 alleles and HTLV-I infection in HAM/TSP patients, HTLV-I carriers and healthy controls in north east of Iran, Mashhad. The blood samples of 16 patients with HAM/TSP, 20 HTLV-1 carriers, and 30 healthy individuals were taken and DNA was extracted by salting out method. HLA-DQB1 typing was performed using PCR-SSP method and the frequency of HLA-DQB1 alleles were compared by Fischer Exact Test. There was a significant difference between HAM/TSP patients and healthy controls in the frequency of HLA-DQB1*07 (P=0.004, RR=7). Furthermore, we found that possession of HLA- DQB1*02 or HLA-DQB1*05 increased the risk of disease 1.5 times. The data presented here suggest that both HLA-DQB1*07 and HLA-DQB1*06 are associated with disease development.

A comparison of HTLV-1 Infection Frequency in Patients with or without Tuberculosis

Introduction: To recognize the predisposing factors in tuberculosis as an endemic infection in Northeast province of Iran, this study was aimed to evaluate whether HumanT-lymphocyte type 1 (HTLV-I) as an immunosuppressive factor increases the risk of tuberculosis. Materials and Methods: A Case-control study was conducted in 278 tuberculosis patients from 2007 to 2010, in Mashhad, Iran. Tuberculosis has been diagnosed by gold standard tests like sputum culture, bronchoalveolar lavage (BAL) culture or cytology. For detection of HTLV-I antibody, Enzyme Linked Immunosorbant Assay method and western Blot as the confirming test were performed. Then 276 healthy cases were matched for gender and age. Results: The mean age of tuberculosis patients was 49.67±21.36 years and for control cases was 48.36±20.74. In patients group, 114 (41.6%) were male, 160 (58.4%) were female and in controls 123 (44.6%) were male and 153 (55.4%) were female. Pulmonary tuberculosis was presented in 84.2% of the patients. The frequency of HTLV-1 was 2.9% and 3.3% in patients and controls, respectively.HTLV-I frequency was higher in male patients and it increased by age. Conclusion: Regarding to this study, HTLV-I infection is not stand-alone sufficient for increasing the risk of tuberculosis.

The complete classification for global dynamics of a model for the persistence of HTLV-I infection

Li and Lim (2011) [8] proposed a three-dimensional system of ordinary differential equations modeling the role of Tax expression in the persistence of Human T-lymphotropic virus Type I and presented a mathematical analysis and its immunovirological explanation. The previous paper shows that three-dimensional system is a cooperative system if a sharp condition is satisfied. By means of the theory of cooperative dynamical systems, they studied the global dynamics. If the sharp condition is not satisfied, they leave it an open problem. The present paper is to provide a complete classification of global dynamics for this ODE model. In particular, our global analysis establishes that the dynamics of the HTLV-I infection are completely determined by a basic reproductive number, which completely solves the open problem above.

130 Reinhard Kurth Honorary Lecture HTLV-I and Adult T Cell Leukemia/Lymphoma (ATLL)

HTLV-I infection is endemic in a number of well defined geographical regions and is associated with the development of ATLL, an aggressive T cell malignancy. While the pathogenesis of ATLL is incompletely understood, the viral regulatory and oncoprotein Tax is considered to play a central role. To better understand the role of Tax and to develop animal models of disease we have generated transgenic mouse models which have remarkably reproduced the clinical, pathological, hematological and molecular features of human disease. Studies on the latter have highlighted the important role of chemokines in the infiltrative and migratory properties of malignant cells, allowed the identification of specific cellular signalling pathways involved and the employment of specific inhibitors as treatment modalities. Treatment responses however have been limited and this can be attributed to the presence of cancer stem cells (CLCs). We will describe the identification and characteristics of the CLCs and demonstrate their important role in disease progression. In addition we will summarise studies employing proteomic approaches to identify unique CLC protein expression profiles which may serve as important targets towards eradicating the CLC population and which might serve as key therapeutics.

Global Hopf branches and multiple limit cycles in a delayed Lotka-Volterra predator-prey model

In recent studies, global Hopf branches were investigated fordelayed model of HTLV-I infection with delay-independent parameters.It is shown in [8,9] that when stability switches occur,global Hopf branches tend to be bounded, and different branches canoverlap to produce coexistence of stable periodic solutions. In thispaper, we investigate global Hopf branches for delayed systems withdelay-dependent parameters. Using a delayed predator-prey model asan example, we demonstrate that stability switches caused by varyingthe time delay are accompanied by bounded global Hopf branches. Whenmultiple Hopf branches exist, they are nested and the overlapproduces coexistence of two or possibly more stable limit cycles.

Evidence of the Human T-cell Lymphotropic Virus (HTLV-I) Circulation in Santiago De Cuba Province (Cuba)

Evidence of the Human T-cell Lymphotropic Virus (HTLV-I) Circulation in Santiago De Cuba Province (Cuba) Human adult T-cell leukaemia and the HTLV-associated myelopathy/tropical spastic paraparesis constitute the indicative main disease of the HTLV-I virus circulation in endemic areas. The objective of this work was to confirm the existence or not of the HTLVI infection in Santiago de Cuba Province where there have not been reported any HTLV seropositive persons up to the present. We studied 1548 sera samples: 1436 blood donors, 35 transfused patients and 77 persons with clinical symptoms associated to this virus. We used enzyme-linked immunosorbent (EIA) and Western blot assays (DAVIH-BLOT HTLV-I (DAVIH Laboratories, Cuba) to detect and confirm the HTLV-I-specific antibodies.

FDC Like Cell Line HK With IL-2, IL-4 and OX40 Ligand Supports The Growth Of ATLL Cells

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive neoplasm derived from CD4+ T-cells with HTLV-I infection, and its mechanisms of tumorigenesis still remain to be elucidated. The fact that tumor cells rarely proliferate in vitro is one of the most important problems to be solved. The establishment of cell line from ATLL patient samples has been difficult even in the presence of interleukins. Previously we established one cell line (HU-ATTAK) from acute or lymphoma types of 10 ATLL cases which did not proliferate in the presence of IL-2 and/or IL-4. HU-ATTAK is critically dependent on IL-2 and human umbilical cord vein endothelial cells (HUVEC) as feeder cells. In HU-ATTAK, adding anti-OX40 ligand antibody into the culture system completely inhibited its proliferation. So, OX40 ligand as well as L-2 and/or IL-4 is suggested be necessary for the proliferation of ATLL cells, and feeder cells may also confer the favorable environment. As the substitute of HUVEC, follicular dendritic cell like cell line HK which expresses OX40 ligand was used by introducing human OX40 ligand cDNA (HK-OX40L). When 9 ATLL patient samples were co-cultured with HK-OX40L in the presence of L-2 and/or IL-4, two ATLL cells proliferate vigorously only in the presence of both IL-2 and IL-4 simultaneously. These cell lines were confirmed to be derived from original tumor cells by array CGH analysis, and continued the growth for more than a year. Depletion of IL-2 and IL-4 made these cell lines stop growing within 6 days even on HK-OX40L. In the presence of IL-2 and IL-4, the conditions such as HK alone without OX40 ligand or OX40 ligand alone without HK made the cell lines growing for three months at most. In the presence of IL-2 and IL-4 without HK-OX40L, these cell lines vigorously proliferated for more than three months but finally stopped growing. These data suggested that for the growth of these two cell lines, the cell division is dependent on IL-2 and IL-4, and the maintenance of immortalization is dependent on OX40 ligand and HK cells. This culture analysis would provide important factors for cell growth of ATLL which will explore new targets for ATLL treatment.*HK cells are kindly provided by Dr. Young S Choi at Ochsner Cancer Center, New Orleans. Disclosures:No relevant conflicts of interest to declare.

HTLV-I infection in the South West Indian Ocean islands, particularly in La Réunion and the Seychelles

Data on HTLV-I are scarce in several Southwest Indian Ocean islands except for La Réunion and The Seychelles. The two cases of HTLV-I have been confirmed by Western-Blot in La Réunion, among blood donors. In Seychelles (87 400 inhabitants in 2012), where blood donors and some other cases are screened, HTLV-I was confirmed with a line immune assay in 43 persons and at least 10-20 patients are known to have tropical spastic paraparesia or adult T-cell lymphoma associated with HTLV-I. In the south-west Indian Ocean, a possibly important other issue may be co-infection of HTLV-1 with the Strongyloides stercoralis roundworm, which is endemic in all countries of the region and which can sometimes lead to severe symptomatic infestation.

In-depth bioinformatic analysis of lung cancer-associated microRNA targets

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide. However, few studies of its specific mechanisms useful for diagnosis or treatment exist. microRNAs (miRNAs) present one mechanism through which genes with diverse functions on multiple pathways can be simultaneously regulated at the post-transcriptional level. However, LC-associated pathways targeted by LC-related miRNAs (LC-miRNAs) remain completely unknown. In the present study, we investigated 8 LC-miRNAs previously identified as regulators in three molecular subtypes of LC. The results showed that LC-miRNAs may post-transcriptionally function mainly through manipulating the expression of nucleic acid binding proteins and transcription factors, and target genes for the LC-miRNAs were most prominently predicted to function in regulation of transcription. Our analysis also highlighted the potential of these LC-miRNAs to regulate the cell differentiation, proliferation, endocytosis and migration signaling logically required to cause an LC cell mainly through five canonical pathways (PI3K-Akt signaling pathway, pathways in cancer, MAPK signaling pathway, HTLV-I infection and focal adhesion). These findings may form a useful basis for potential future development of novel LC therapeutic treatments.

Global stability of a delayed HTLV-I infection model with a class of nonlinear incidence rates and CTLs immune response

In this paper, applying new Lyapunov functional techniques to a delayed HTLV-I infection model with a class of nonlinear incidence rates and CTLs immune response, we establish that the global dynamics are completely determined by two basic reproduction numbers R0>R0∗, as follows. If R0⩽1, then a viral-free equilibrium is globally asymptotically stable, if R0∗⩽1<R0, then there exists a unique no-immune response equilibrium is globally asymptotically stable, and if R0∗>1, then there exists a unique endemic equilibrium which is globally asymptotically stable. In particular, to obtain concrete eventual lower bounds for positive solutions of the model we offer some new techniques.