Marina Lobato Martins

Infecção e doença pelos vírus linfotrópicos humanos de células T (HTLV-I/II) no Brasil

HTLV-I/II infection is present in all regions of Brazil, but its prevalence varies according to the geographical area, being higher in Bahia, Pernambuco and Pará. It has been estimated that Brazil has the highest absolute number of infected individuals in the world. Blood donors screening and research conducted with special groups (indigenous population of Brazil, IV drug users and pregnant women) are the major sources of information about these viruses in our Country. HTLV-I causes adult T cell leukemia/lymphoma (ATLL), HTLV associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV associated uveitis (HAU), dermatological and immunological abnormalities. HTLV-II is not consistently associated with any disease. Diagnosis is established using screening (enzymatic assays, agglutination) and confirmatory (Western blot, PCR) tests. The viruses are transmitted by blood and contaminated needles, by sexual relations and from mother to child, especially by breast feeding. Prevention efforts should focus on education of positive blood donors, infected mothers and IV drug users.

HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Inflammatory Network

HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is a systemic immune-mediated inflammatory disease and tissues other than nervous can be damaged, mainly ocular, rheumatic and dermatologic. Over 90% of HTLV-1-infected individuals remain lifelong asymptomatic and this retrovirus persists indefinitely in their CD4+ T-lymphocytes. The infection is maintained due to the proliferation of lymphocytes that harbor a provirus and express HTLV-1 proteins, particularly Tax, promoting an active and selective expansion of infected T cells. High proviral load is related to disease progression, which is correlated to disequilibrium between host and virus. Cytotoxic T lymphocytes are abundant and chronically activated in asymptomatic carriers and in HAM/TSP patients. The asymptomatic carriers were shown to have a high frequency of pro-inflammatory monocytes and anti-inflammatory IL-10+CD4+ and IL-10+CD8+ T-cells, as an immunoregulatory mechanism to counterbalance the monocyte-derived TNF-alpha. A putative immunomodulatory event would be the key to control their overall immunological status. In HAM/TSP, a pro-inflammatory microenvironment is the hallmark of the immunological profile. Enhanced frequency of activated CD8+ T-cells (HLA-DR+) in combination with high CD18 surface expression has been seen. In blood and cerebrospinal fluid, increased levels of Type-1 cytokines, as interferon-(IFN)-gamma, Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL)-2, and pro-inflammatory IL-6, can be found. Concerning the progression, HLA polymorphisms may influence HAM/TSP and the allele HLA-A*2 has been associated with protection. The authors showed that HAM/TSP is strongly associated with a decreased percentage of B-cells, with enhanced T/B-cell ratio and activated CD8+ T-cells. These immunological parameters have been proposed as a prognostic biomarker for HAM/TSP.

Monitoring the HTLV-1 proviral load in the peripheral blood of asymptomatic carriers and patients with HTLV-associated myelopathy/tropical spastic paraparesis from a Brazilian cohort: ROC curve analysis to establish the threshold for risk disease.

Human T‐lymphotropic virus 1 (HTLV‐1) infection is associated with HTLV‐associated myelopathy/tropical spastic paraparesis (HAM/TSP), which affects approximately 5% of carriers. High proviral load is a risk marker for HAM/TSP, although there is an overlap of proviral load levels in peripheral blood between asymptomatic carriers and HAM/TSP patients. In this study, receiver operating characteristic curve analysis was used to define a set point of HTLV‐1 proviral load that better indicates an increased risk for HAM/TSP. Proviral load was quantified in 75 asymptomatic carriers and 78 HAM/TSP patients in a Brazilian cohort. The cut‐off of proviral load was defined as 114 copies/104 cells, with 78.2% sensitivity to identify true HAM/TSP patients. The mean proviral load levels were not significantly different between males and females with the same clinical status, and there was no significant correlation between proviral load and age at blood sampling, age at the onset of illness, or duration of disease. In HAM/TSP patients, proviral load was significantly higher in wheelchair‐bound patients than in individuals able to walk without support and in those with the worst spinal cord injuries. Follow‐up of HTLV‐1‐infected individuals showed that proviral load was more stable in asymptomatic carriers than in HAM/TSP patients. In a cohort study, periodically quantifying proviral load in asymptomatic carriers is necessary to identify those at risk for developing neurological disease, and it is necessary for HAM/TSP patients to monitor spinal injury and progression to walking disability. The measure of proviral load in clinical practice implicates the definition of the cut‐off of proviral load and its validation during follow‐up. J. Med. Virol. 84:664–671, 2012.

Proviral load and the balance of serum cytocines in HTLV-1-asymptomatic infection and in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

This study compared the proviral load and the plasma cytokine profiles (interleukin-IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) in 87 HTLV-1-infected individuals, including 28 with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), 32 with possible pHAM/TSP and 27 asymptomatic carriers (AC). The control group was composed by 21 HTLV-1-seronegative individuals. Our finding demonstrated that HAM/TSP group presented higher proviral load as compared to all other HTLV-1 groups (p<0.0001). The HAM/TSP group showed higher serum concentration of IL-6 (p=0.0009) as compared to all other groups. Moreover, higher serum concentration of IFN-γ (p=0.0118) and IL-4 (p=0.0166) were observed in HAM/TSP group as compared to the healthy controls. Additionally, the HAM/TSP group also showed higher serum concentration of TNF-α (p=0.0239) and IFN-γ (p=0.0118) as compared to AC. No differences in the serum concentration of IL-2 and IL-10 were observed among the groups. The analysis of cytokine balance demonstrated that HAM/TSP presented higher pro-inflammatory profile with enhanced IFN-γ/IL-10 and IFN-γ/IL-4 ratio as compared to AC and pHAM/TSP. Further analysis pointed out to a positive correlation between the IFN-γ response and the proviral load in AC. Conversely, a negative association between TNF-α and IL-2 with the proviral load was the hallmark of HAM/TSP group. These findings suggested that the proviral load and the pro-inflammatory cytokine profile may be independent events in the peripheral blood of HAM/TSP individuals. The knowledge about the existence of individual virological/immunological behavior upon HTLV-1 infection, may guide to the establishment of more effective therapeutic interventions.

Dermatological Findings in 3 Generations of a Family with a High Prevalence of Human T Cell Lymphotropic Virus Type 1 Infection in Brazil

BACKGROUND Dermatologic manifestations are quite common in patients with adult T cell leukemia and lymphoma and patients with myelopathy and/or tropical spastic paraparesis associated with human T cell lymphotropic virus type 1 (HTLV-1). The aim of this study was to investigate dermatological findings presented by 30 members of a Brazilian family, half of whom are infected with HTLV-1 (as confirmed by enzyme-linked immunosorbent assay and Western blot). METHODS The subjects underwent dermatologic examination and laboratory assessment, which included the search for the HTLV-1 genome in peripheral blood mononuclear cells (PBMCs) by qualitative and semiquantitative polymerase chain reaction (PCR) and in skin samples by nested qualitative PCR and immunofluorescence assay. RESULTS We found that cases of xerotic dermatological alterations, including 3 cases of acquired ichthyosis, were more frequent among the infected patients (7 cases vs. none among the uninfected individuals; P=.0063). Other lesions observed in this group included impetigo, scabies, epidermal nevus, herpes zoster scar, rosacea, and juvenile acne. One HTLV-1-infected individual presented with concurrently acquired ichthyosis, impetigo, scabies, dermatophytosis, and seborrheic dermatitis. The PCR performed on PBMCs and skin samples from 24 patients confirmed the serological results in all cases. Additionally, the HTLV-1 proviral load was higher in patients with >1 skin lesion. Finally, HTLV-1 could be identified in the skin by immunofluorescence assay, which, by use of PCR as the gold standard, showed a sensitivity and specificity of 61.5% and 100%, respectively. CONCLUSIONS Altogether, these clinical and laboratory findings point to an HTLV-1 tropism toward the skin, even in HTLV-1 carriers without adult T cell leukemia/lymphoma or HTLV-1-associated myelopathy and/or tropical spastic paraparesis.

Lesões dermatológicas em pacientes infectados pelo vírus linfotrópico humano de células T do tipo 1 (HTLV-1)

Human T-cell Lymphotropic virus type I (HTLV-1) was the first human retrovirus described. Some time after its discovery a group of diseases were related to this virus, such as, adult T-cell leukemia lymphoma (ATLL), HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1 associated uveitis (HAU). In the nineties, HTLV-1 was associated to a severe eczema of children, called infective dermatitis (ID). Since then, several other skin manifestations have been observed in HTLV-1-infected individuals, particularly in patients with ATLL or HAM/TSP. However, according to some reports, dermatologic lesions are also common in asymptomatic HTLV-1 carriers. Besides ID, all other skin lesions reported are nonspecific. The aim of this review is to outline the dermatologic manifestations reported in HTLV-1 infected patients, emphasizing the clinical and epidemiological value of these findings.

Increased Prevalence of Human T Cell Lymphotropic Virus Type 1 in Patients Attending a Brazilian Dermatology Clinic

Brazil may have the highest absolute number of individuals infected by human T cell lymphotropic virus type 1 (HTLV-1). It has been suggested that the prevalence of HTLV-1 is increased in patients with skin diseases. This study shows a higher prevalence of this infection in 1,229 patients attending a Brazilian dermatology clinic (0.7%) when compared to blood donors (0.22%). Of note, one additional patient tested positive for HTLV-2. The main skin diseases described in HTLV-1 seropositives were vitiligo (2 cases), dermatophytosis (2 cases), and leprosy (2 cases). A 23-year-old woman received a diagnosis of infectious dermatitis.

Strong correlation between tax and HBZ mRNA expression in HAM/TSP patients: Distinct markers for the neurologic disease

BACKGROUND HTLV-1 proviral load is a risk marker for HAM/TSP, but it is insufficient to determine the disease outcome. HTLV-1 Tax and HBZ proteins have been implicated in HAM/TSP pathogenesis in inducing cell proliferation and cytotoxic T lymphocytes response. OBJECTIVES To quantify the expression of tax and HBZ mRNA in asymptomatic carriers (AC) and HAM patients, and to investigate their association with HAM/TSP. STUDY DESIGN We quantified the expression of HTLV-1 tax and HBZ mRNA in 37 AC and 26 HAM patients classified according to proviral load as low (AC(L) and HAM(L): <1% infected cells) or high (AC(H) and HAM(H): >1%). RESULTS The AC(L) subgroup showed the lowest frequency of individuals expressing tax mRNA in comparison with AC(H), HAM(L) and HAM(H), and tax mRNA load normalized by proviral load was significantly lower in the AC(L). In turn, normalized HBZ mRNA expression was similar in all subgroups. Both tax and HBZ mRNA expression were moderately correlated with proviral load in AC (r=0.6, p<0.001) and were weaker in HAM (r=0.4, p<0.05). In contrast, the correlation between tax and HBZ mRNA load was moderate in AC (r=0.5, p=0.001) and was much stronger in HAM (r=0.8, p<0.001). In addition, HBZ mRNA load, but not tax, was significantly associated with motor disability in HAM patients (p=0.036). CONCLUSIONS The expression of tax mRNA seems to be best to estimate the risk of HAM/TSP, whereas HBZ mRNA appears to be a surrogate marker to disease progression, indicating that they have important but distinct roles in HAM/TSP pathogenesis.

High prevalence of HTLV-1 and 2 viruses in pregnant women in São Luis, state of Maranhão, Brazil.

INTRODUCTION Human T cell lymphotropic virus type 1 (HTLV-1) is endemic in the Caribbean, Japan, South America and regions of Africa. HTLV-2 is present in Native American populations and associated with IV drug use in Europe and North America. In Brazil, it is estimated that 1.5 million people are infected with HTLV-1/2. The study objective was to determine HTLV-1/2 prevalence in pregnant women in the prenatal care from three public services in São Luis, State of Maranhão, Brazil, and to counsel seropositive women to reduce viral transmission. METHODS A cross-sectional study was conducted from February to December 2008; women with age of 18 to 45 years, with low risk for sexually transmitted disease (STD) were invited to participate. Blood samples were collected in filter paper, and HTLV-1/2 immunoenzymatic test (ELISA) was performed as a screening test. Women with reactive results were submitted to peripheral venous blood collection for ELISA repetition, followed by Western blot (WB) and real-time PCR to confirm and discriminate the infection between virus types 1 and 2. RESULTS Of the 2,044 women tested, seven (0.3%) were ELISA reactive and confirmed positive (four were HTLV-1, and three were HTLV-2). All positive women were oriented not to breastfeed their newborns. CONCLUSIONS This study showed that the virus is present in high prevalence in that population. Further studies covering other segments of the population are necessary to better characterize the presence of HTLV-1/2 in Maranhão and to elicit measures to prevent its spread.

Extensive admixture in Brazilian sickle cell patients: implications for the mapping of genetic modifiers.

To the editor: Genome-wide association studies (GWASs) of sickle cell disease (SCD) patients are a promising tool for identifying genetic modifiers of clinically relevant traits.[1][1],[2][2] In such a study, Solovieff et al[2][2] have uncovered a set of SNPs associated with fetal hemoglobin (HbF)