Frequent reversible membrane damage in peripheral blood B cells in human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Apoptosis in peripheral blood lymphocyte populations in HTLV-I-infected people in vivo was examined, to study the lymphocyte dynamics in HTLV-I infection. Freshly isolated lymphocytes from 10 non-infected healthy people, eight asymptomatic HTLV-I carriers and 15 patients with HAM/TSP were stained with FITC-labelled annexin V to detect phosphatidylserine (PS) residue exposure at the outer plasma membrane leaflet as an early marker of apoptosis. There was no significant difference in annexin V positivity in CD4+ and CD8+ lymphocytes between non-infected subjects, asymptomatic carriers and HAM/TSP patients, but there was a greatly increased exposure of PS on CD19+ lymphocytes (B cells) detected by FITC-annexin V in 12 out of 15 (80%) HAM/TSP patients, while only two out of eight (25%) asymptomatic carriers and none of the non-infected healthy people showed this aberrant PS exposure on B cells. The intensity of annexin V staining of B cells in HAM/TSP was intermediate, as distinct from the high annexin V staining on advanced apoptotic cells. However, annexin V positivity was decreased when the cells were stained after 24 h of culture, suggesting that the intermediate PS exposure on the B cell in HAM/TSP is not a consequence of an apoptotic process, but rather reflects reversible membrane damage. B cells with PS exposure in vivo might provide a site for coagulation and inflammation, and so contribute to the pathogenesis of HAM/TSP and its complications.     

Cell-mediated immune response to human T-lymphotropic virus type I

Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that causes persistent infection in many populations in tropical and subtropical regions. HTLV-I chronically activates the cell-mediated arm of the host adaptive immune response. There has been much debate about the role of the immune response in determining the outcome of HTLV-I infection: most seropositive individuals remain lifelong asymptomatic carriers of the virus, whereas a small proportion-usually those with higher equilibrium proviral loads-develop an inflammatory disease of the central nervous system known as HAM/TSP. Here we discuss the cell-mediated immune response to HTLV-I infection. We summarize recent data on the HTLV-I-specific CD4(+) cell response and explore its potential role in HAM/TSP pathogenesis. We also explore the controversy surrounding the role of the CD8(+) cell response in controlling HTLV-I infection and/or contributing to HAM/TSP disease, highlighting recent studies of T cell gene expression profiles and a newly developed assay of CD8(+) cell functional efficiency. Finally, we introduce a possible role for cellular innate immune effectors in HTLV-I infection.     

Human T-lymphotropic virus type I (HTLV-I)-specific CD8+ cells accumulate in the lungs of patients infected with HTLV-I with pulmonary involvement

Pulmonary involvement has been identified in human T-lymphotropic virus type I (HTLV-I) carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the relationship between HTLV-I infection and lung disease is poorly understood. The occurrence of HTLV-I-specific immune responses in the lungs of patients infected with HTLV-I with pulmonary involvement was investigated. The frequency of HTLV-I-specific CD8+ cells and the amount of HTLV-I proviral DNA were determined in bronchoalveolar lavage fluid cells and peripheral blood mononuclear cells (PBMCs) from five patients with HAM/TSP and one HTLV-I carrier who had pulmonary involvement. HTLV-I-specific CD8+ cells were detected by flow cytometry using human leukocyte antigen/antigen complex multimers. The analysis of bronchoalveolar lavage fluid revealed lymphocytosis in five of six patients. HTLV-I provirus was detected in the bronchoalveolar lavage fluid cells of all patients, and the proviral load in these cells was comparable to that in PBMCs. The frequency of HTLV-I-specific CD8+ cells in the bronchoalveolar lavage fluid cells was 5.1 times higher than that in PBMCs. Immunohistochemically, clusters formed by HTLV-I-specific CD8+ cells were detected in lung tissue by in situ tetramer staining. No samples were available from patients infected with HTLV-I without lung disorders. Whether accumulation of CD8+ cells is specific to patients with pulmonary involvement remains unclear. These results indicate that HTLV-I-specific CD8+ cells accumulate and HTLV-I-infected cells exist in the lungs of patients infected with HTLV-I with pulmonary involvement.     

Association of CD40 ligand expression on HTLV-I-infected T cells and maturation of dendritic cells

Human T lymphotropic virus type I (HTLV-I) induces HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). The development of HAM/TSP is associated with rapid maturation of dendritic cells (DCs), while ATL is accomplished with their maturation defect. The DC maturation is induced by cell-to-cell contact with CD4+ T cells expressing CD40 ligand (L). We determined the influence of CD40L expressed on various HTLV-I-infected T cells on the DC maturation. Around 60% of CD4+ T cells infected with HTLV-I for 1 week, expressed CD40L molecules involved in DC maturation. DCs matured by the CD40L+ T cells activated autologous CD4+ and CD8+ T cells. HTLV-I-immortalized T-cell lines established from healthy donors consistently expressed CD40L molecules for 3 months, however, some lines lost the expression soon thereafter. Interleukin (IL)-2-independent and transformed lines lacked that expression. Furthermore, T cells obtained from HAM/TSP patients expressed CD40L molecules for at least 3 weeks, whereas T cells from ATL patients did not express that. The CD40L T cells did not induce DC maturation, and required exogenous CD40L molecules for maturation. The CD40L+ T-cell-induced maturation was blocked by anti-CD40L antibody. Therefore, the lack of CD40L expression on HTLV-I-infected T cells may be associated with the development of ATL.     

Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells

We established long-term cell lines of cytotoxic T lymphocytes (CTL) specific for human T cell leukemia virus type I (HTLV-I) from peripheral blood lymphocytes (PBL) of a patient with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an HTLV-I-carrier with Sj?gren syndrome, and an asymptomatic HTLV-I-carrier, by repeated stimulation with autologous HTLV-I-infected T cells in vitro. CTL derived from the patient with HAM/TSP expressed CD8 antigen, and their function was restricted by HLA-A2. They showed cytotoxic effects predominantly against the target cells expressing HTLV-I p40tax among the autologous B cell lines infected with vaccinia recombinants containing various HTLV-I genes which served as targets. These data are consistent with the previously reported findings that fresh PBL of HAM/TSP patients contain p40tax-specific CTL activity. Furthermore, CTL derived from the patient with Sj?gren syndrome without neurological involvement also demonstrated cytotoxicity predominantly to p40tax. The cytotoxicity to the target cells experimentally expressing p40tax was blocked by unlabeled HTLV-I-infected cells possessing HLA-A2. HTLV-I-specific cytotoxicity was also inhibited by unlabeled B cells bearing p40tax. Thus, HTLV-I p40tax-specific cytotoxicity is mediated by the major CTL population activated by native HTLV-I antigens in patients with HAM/TSP or Sj?gren syndrome. In contrast to the CTL of these patients, CTL similarly induced from the asymptomatic HTLV-I-carrier, which were highly cytotoxic to autologous HTLV-I-infected T cells, did not show significant levels of cytotoxicity to autologous B cells expressing p40tax.(ABSTRACT TRUNCATED AT 250 WORDS)     

Programmed death-1 (PD-1)/PD-1 ligand pathway-mediated immune responses against human T-lymphotropic virus type 1 (HTLV-1) in HTLV-1-associated myelopathy/tropical spastic paraparesis and carriers with autoimmune disorders

Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A*0201 tetramer and an HTLV-1 Tax/HLA-A*2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A*2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A*0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1.     

Concomitant augmentation of CD4+ CD29+ helper inducer and diminution of CD4+ CD45RA+ suppressor inducer subset in patients infected with human T cell lymphotropic virus types I or II.

To examine the immunomodulatory effects of HTLV infection, lymphocyte subset analysis was performed on patients infected with human T cell lymphotropic virus type-I (HTLV-I, n = 6) or -II (HTLV-II, n = 12) and on normal blood donors (n = 16). The percentages of total B lymphocytes (CD19), natural killer (NK) cells (CD16), T lymphocytes and their subsets (CD2, CD3, CD4, CD5, CD7, CD8), and IL-2R (CD25) were found to be within the range found in normal donors. However, the expression of CD8+ HLA-DR+ increased significantly in patients with HTLV-I or HTLV-II infection (14.1 +/- 3.9% and 9.7 +/- 2.4% respectively; P less than 0.01) when compared with controls (3.2 +/- 1.1%). In addition, there was a significantly greater proportion of CD4+CD29+ T lymphocytes (29.3 +/- 6.1% and 31.1 +/- 9.0%; P less than 0.05) with concomitant diminution of CD4+CD45RA+ T lymphocytes (8.3 +/- 3.3% and 11.4 +/- 1.5%; P less than 0.01) in patients infected with HTLV-I or HTLV-II respectively, when compared with controls. The increased percentage of CD4+CD29+ subpopulations showed a direct correlation (rs = 0.86; P less than 0.001) with HTLV-specific antibody production. No difference in the CD8 population coexpressing CD29 and S6F1 (an epitope of LFA-1) were observed in the HTLV-infected group when compared with normal donors and functional analysis exhibited minimal cytotoxicity against lectin labelled heterologous target cells. Thus, the shift in the suppressor/cytotoxic to helper/inducer 'memory' CD4+ may be associated with immunoregulatory abnormalities often found in persons infected with HTLV-I or HTLV-II.     

Importance of immune deviation toward Th1 in the early immunopathogenesis of human T-lymphotropic virus type I-associated myelopathy

Although the principal neuropathological feature of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) is chronic inflammation of the spinal cord, characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration, the precise mechanisms by which HTLV-I infection causes chronic inflammation of the spinal cord are still obscure. In patients with HAM, peripheral blood CD4(+)T lymphocytes, particularly HTLV-I-infected CD4(+)T lymphocytes, have increased adherent activity to endothelial cells and transmigrating activity through basement membranes. In addition, the profile of cytokine expression suggests increased numbers of Th1 cells in peripheral blood CD4(+)T lymphocytes of patients with HAM. These findings strongly suggest that immune deviation toward Th1, which might be based on high viral load of HTLV-I, plays an important role in tissue damage in the central nervous system of patients with HAM. We herein emphasize the importance of activated Th1 cells as the first trigger in the immunopathogenesis of HAM.     

Reflux of HTLV-I infected lymphocytes from the privileged compartment(s) to peripheral blood flow in patients with HTLV-I-associated myelopathy

 To understand the mechanisms involved in the pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), three in vivo phenomena which have been observed in the peripheral blood of patients and differing from that in asymptomatic HTLV-I carriers must be taken into consideration: (a) the presence of increased HTLV-I viral load, (b) a higher immune responsiveness against HTLV-I antigens, and (c) biased nucleotide substitutions in the HTLV-I pX region which indicate a decreased selection pressure for viral amino acid changes. We now propose a hypothesis which focuses on the in vivo dynamics of HTLV-I infected lymphocyte migration and which incorporates these features. In addition, the hypothesis assumes the existence of a deviation in immune surveillance for HTLV-I in the central nervous system (CNS) in spite of the presence of frequent specific immune effectors. We suggest that in the active phase of HAM/TSP, accompanied with or following autoaggressive interactions between infected lymphocytes and immunocompetent cells in the CNS, there is a consequential reflux of the infected lymphocytes to the peripheral blood. The reflux of infected cells would be expected to provide peripheral blood with tissue-derived HTLV-I proviruses which have been indulged and propagated in an immune-privileged site. This process would result in and account for the observed increase in viral load and the substitution bias in HTLV-I sequences in the peripheral blood. Received: 31 January 1997 / Accepted: 17 June 1997     

T cell activation and disease severity in HIV infection.

In vitro studies have indicated that T lymphocyte activation may be of importance in the pathogenesis of HIV infection. In order to define the role of immune activation in vivo, we assessed the expression of the T cell activation markers HLA-DR and CD25 by flow cytometry in peripheral blood in relation to disease severity and the surrogate markers CD4 and beta 2-microglobulin in 157 patients with HIV infection and 53 healthy seronegative blood donors. Percentage levels of CD3+HLA-DR+ T lymphocytes were significantly higher (P < 0.0001) and percentage levels of CD3+CD25+ T lymphocytes significantly lower (P < 0.0001) in all HIV+ patients compared with controls. A significant correlation was observed between increasing percentage levels of CD3+HLA-DR+ T lymphocytes and both declining CD4 counts (r = 0.52; P < 0.001) and increasing beta 2-microglobulin levels (r = 0.56; P < 0.001). Percentage levels of CD4+HLA-DR+ and CD4+ CD25+ lymphocytes were significantly higher in all HIV+ patients compared with controls (P < 0.001). Levels of activated (HLA-DR+ and CD25+) CD4+ lymphocytes showed a significant step-wise linear increase with increasing disease severity (P < 0.001). High levels of CD3+HLA-DR+ T lymphocytes were found in a greater proportion (81.8%) of asymptomatic HIV+ patients (Centres for Disease Control (CDC) group II) than low CD4 counts (51.5%) (P < 0.001). Compared with controls, HIV+ patients had higher percentage levels of CD8+HLA-DR+ lymphocytes (P < 0.001), but similar levels of CD8+CD25+ lymphocytes. These results indicate that T cell activation is not only a consistent but also an early feature in HIV infection. Monitoring levels of activated T cells and their subsets is of value in assessing progression of HIV-related disease.     

IL-10 produced by CD4+ and CD8+ T cells emerge as a putative immunoregulatory mechanism to counterbalance the monocyte-derived TNF-alpha and guarantee asymptomatic clinical status during chronic HTLV-I infection

Although it is believed widely that distinct patterns of the host immune response are associated with the outcome of chronic human T cell lymphotropic virus type 1 (HTLV-I) infection toward asymptomatic or symptomatic neurodegenerative myelopathy (HAM/TSP), the exact mechanism underlying these immunological events still remains unknown. In this study, we have evaluated the cytokine pattern [interleukin (IL)-12, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, IL-4 and IL-10] of innate and adaptive immunity cells present at the peripheral blood from non-infected (NI) and HTLV-I infected individuals [asymptomatic (AS), oligosymptomatic (OL) and HAM/TSP-HT], following in vitro short-term incubation in the absence/presence of phorbol myristate acetate (PMA) pan-leucocyte stimulation. In the absence of PMA stimulation, our data demonstrate that despite the overall immunological profile of AS mimicry that observed for NI, the high frequency of IL-12(+) neutrophils and TNF-alpha(+) monocytes are also a hallmark of this group of individuals. However, the outstanding positive correlation between the high frequency of TNF-alpha(+) monocytes and high levels CD4(+) IL-10(+) and CD8(+) IL-10(+) T cells suggests the establishment of immunoregulatory mechanisms that guarantee their asymptomatic clinical status. On the other hand, OL and HT did not present any association between the high frequency and TNF-alpha(+) neutrophils and monocytes and this immunoregulatory profile at their adaptive immunity cells. Upon PMA-index analysis, high levels of type 1 CD4(+) T cells, as well as higher IFN-gamma/IL-10 and TNF-alpha/IL-10 ratios, were observed in HT, and re-emphasize the role of Th1-cytokines from CD4(+) cells to HTLV-I immunity and disease. Moreover, increasing frequency of CD8(+) IFN-gamma(+) and CD8(+) TNF-alpha(+) cells were observed in the HT, which corroborates the marked inflammatory profile underlying this pathological condition and the role of CD8(+) T cells in the pathogenesis of HAM/TSP.     

HTLV-1 in mouthwash cells from a TSP/HAM patient and asymptomatic carriers

Summary.  Using in situ hybridization, the presence of T-cell lymphotrophic virus type I (HTLV-I) was shown in blood lymphocytes of one tropical spastic paraparesis (TSP/HAM) patient and in two asymptomatic carriers. HTLV-I was also detected in epithelial cells derived from mouthwash of the TSP/HAM patient. Mouthwash of one of the carriers showed an infected lymphocyte while mouthwash of the other carrier was negative. The infected epithelial cells stained both in the nucleus and in the cytoplasm, which indicated the presence of the virus in both subcellular compartments. Our observations suggest that saliva cells, lymphocytes and epithelial cells, may potentially participate in oral transmission of HTLV-I. Accepted November 18, 1997 Received August 27, 1997     

Cell cycling in HIV infection: analysis of in vivo activated lymphocytes.

Infection with HIV results in increased circulating levels of T lymphocytes expressing phenotypic markers of immune activation. In the present study, using three-colour immunofluorescence, we examined the cell cycle status of these activated cells. Activated (HLA-DR+, CD25+ and CD38+) CD4+ and CD8+ T lymphocytes in peripheral blood were analysed for DNA content in 15 HIV+ patients and 10 healthy age- and sex-matched control subjects. As expected, all HIV+ patients had elevated percentage levels of activated CD4+ HLA-DR+, CD4+ CD25+, CD8+ HLA-DR+, CD8+ CD25+ and CD8+ CD38+ T lymphocytes compared with control subjects (P < 0.001 for all). Percentage levels of CD4+ HLA-DR+ and CD8+ HLA-DR+T lymphocytes in the 'proliferative' (S-G2M) phase of the cell cycle were also higher in the HIV+ patients compared with controls (P < 0.001 for both). The percentage levels of proliferative CD4+ CD25+, CD8+ CD25+ and CD8+ CD38+ lymphocytes were, however, similar in HIV+ patients and controls, indicating that the proliferative fraction of cells in vivo was confined to the HLA-DR+ subset and absent from the CD25+ and CD38+ populations. Four HIV+ patients had grossly elevated levels of CD8+ lymphocytes which were CD38+ (> 95%) and confined to the pre-G0-G1 phase of the cell cycle, suggesting these may be cells committed to apoptosis. These observations indicate an increase in the proliferative capacity of HLA-DR+ T lymphocytes in HIV infection in vivo. The reduced DNA content in other populations (e.g. CD38+ CD8+ lymphocytes) of some patients with advanced HIV disease suggests that these cells are apoptotic. Thus our results define both proliferative and apoptotic processes as a spectrum of activation-related events in HIV infection.     

Human T cell leukemia virus type I Tax activates CD40 gene expression via the NF-kappa B pathway

The human T cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is etiologically linked to the genesis of adult T cell leukemia (ATL) as well as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Emerging evidence suggests that the pathogenicity of HTLV-I involves deregulated activation of immune cells, especially T lymphocytes, although the underlying mechanism remains unclear. In this study, we demonstrate that HTLV-I Tax induces the aberrant expression of CD40, a member of the tumor necrosis factor receptor (TNFR) family that plays an important role in lymphocyte activation and differentiation. In a panel of HTLV-I-transformed T cell lines analyzed, CD40 expression was highly elevated compared to HTLV-I-negative T cells. Using Tax mutants and a genetically manipulated T cell system, we demonstrated that Tax-induced CD40 expression required the NF-kappaB signaling pathway. In addition, ligation of CD40 on T cells with recombinant CD40L elicited NF-kappaB activation, suggesting that the CD40 pathway is intact and may participate in a positive regulatory loop in T cells. CD40 ligation strongly synergized with Tax to activate NF-kappaB, suggesting that CD40 signals may costimulate Tax-mediated NF-kappaB activation, particularly when Tax is expressed at low levels. Collectively, these results indicate that CD40 is a novel Tax-regulated gene, and the regulation of CD40 by Tax may play a role in cellular activation and HTLV-I-induced disease pathogenesis.     

Target epitopes of HTLV-1 recognized by class I MHC-restricted cytotoxic T lymphocytes in patients with myelopathy and spastic paraparesis and infected patients with autoimmune disorders

Human T-cell lymphotropic virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The different patterns of clinical diseases are thought to be linked to immunogenetic host factors. A variety of autoimmune diseases, such as Sj?gren's syndrome, have been reported in persons infected with HTLV-1, although the precise relationship between these disorders and HTLV-1 infection remains unknown. There is no report on the repertoire of HTLV-1-specific CD8+ T-cells in HAM/TSP patients or carriers with autoimmune diseases, both characterized by an abnormal immune state. In this study, to characterize HTLV-1-specific CD8+ T-cells in asymptomatic HTLV-1 carriers, HAM/TSP patients and carriers with autoimmune diseases, we examined the frequency and diversity of HTLV-1-specific CD8+ T-cells using HTLV-1 tetramers. HTLV-1 Env-specific CD8+ T-cells were significantly more frequent in HAM/TSP and carriers with autoimmune diseases compared with asymptomatic HTLV-1 carriers, while the frequency of HTLV-1 Tax-specific CD8+ T-cells was not significantly different among them. CD8+ cells binding to HTLV-1 Tax tetramers in carriers with autoimmune diseases were significantly reduced compared with HAM/TSP patients. This study demonstrates the importance of CD8+ T-cells recognizing HTLV-1 Env-tetramers in HAM/TSP patients and carriers with autoimmune diseases, thereby suggesting that the diversity, frequency and repertoire of HTLV-1 Env-specific CD8+ T-cell clones may be related to the hyperimmune response in HAM/TSP and carriers with autoimmune diseases, although different immunological mechanisms may mediate the hyperimmunity in these conditions.     

Aberrant Immunity in the Central Nervous System in Relation to Disease Progression in HAM/TSP

The immunological status of the central nervous systems of 19 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was distinct from that of 6 asymptomatic HTLV-I carriers. Cross-sectional analysis of the time course of disease-related abnormalities in the cerebrospinal fluid (CSF) showed that activated B cell function was a feature in relatively early HAM/TSP patients in whom duration of the disease was less than 5 to 6 years. During this period many patients experienced notable neurological deterioration. By contrast, an increase in CD8⁺CD11a⁺cytotoxic T lymphocytes along with elevated β₂-microglobulin levels in the CSF was a consistent finding in early as well as late patients with more than a 10-year history of the illness. In light of the generally progressive course of this disorder, the mode of immunity related to the pathogenesis of HAM/TSP may be different according to the stages of the disease.     

Lower CD4+ T Lymphocyte Nadirs May Indicate Limited Immune Reconstitution in HIV-1 Infected Individuals on Potent Antiretroviral Therapy: Analysis of Immunophenotypic Marker Results of AACTG 5067

Background: Although initiation of potent antiretroviral therapy (ART) has significantly improved immune perturbations in individuals with AIDS, it is unclear which factors are most important in determining the degree of immune reconstitution.Methods: Whole blood was analyzed at baseline and week 12 in six groups of subjects (n = 81): those with acute or following immune reconstitution after Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia (PcP) (two groups) and cytomegalovirus (CMV) retinitis (two groups), HIV-infection without AIDS (one group), and healthy volunteers (one group). Absolute CD4+ and CD8+ T lymphocytes, naíve (CD45RA+) and memory (CD45RO+) CD4+ T lymphocytes and percentages of activated CD8+ T lymphocytes (CD8+/CD38+/HLA-DR), and CD28 expression on CD4+ and CD8+ T lymphocytes were enumerated.Results: The reconstituted CMV group, which had a history of a lower CD4+ T lymphocyte nadir compared to the reconstituted PcP group (15 cells/mm³ versus 48 cells/mm³; p = .013), had significantly lower absolute CD4+, CD8+ and naíve CD4+ T lymphocytes and a trend toward lower memory CD4+ T lymphocytes compared to the reconstituted PcP group. Moreover, no difference was noted between the reconstituted groups in the proportion of subjects with undetected HIV-1 RNA. The reconstituted subjects had significantly lower absolute CD4+, memory CD4+ and naíve CD4+ T lymphocytes than the HIV-positive controls and a significantly higher percentage of activated CD8+ T lymphocytes with a lower percentage of CD8+CD28 expression than the HIV-negative controls.Conclusion: The association of CD4+ T lymphocyte nadir with the extent of immune reconstitution in HIV-infected individuals suggests that HIV-1 may cause irreparable immune system damage despite potent ART.     

Presence of HTLV-I Tax protein in cerebrospinal fluid from HAM/TSP patients

Summary. Infection with human T-cell lymphotropic virus type I (HTLV-I) have been associated with the development of the HTLV-I-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). The disease affects the pyramidal tract at the distal segments of spinal cord, generating a spastic paraparesis. We studied the presence of Tax protein in cerebrospinal fluid cells and spinal fluid (CSF) of 35 Chilean patients: 22 HAM/TSP patients (15 HTLV-I-seropositives, and 7 seronegatives), and 13 controls (9 PSP and 4 CJD non-infected patients). Tax antigens were evaluated with monoclonal antibodies reacting with Tax by immunofluorescence and ELISA assays in cerebrospinal fluid cells and CSF, respectively. Proviral was evaluated by PCR of tax gene in cerebrospinal fluid cells. Tax antigen was detected in CSF and lymphocytes of CSF from 4 and 12 HAM/TSP patients, respectively. Lymphocytes of CSF of 8 HAM/TSP (6 seropositives and 2 seronegatives) showed the presence of tax gene. These results show that cells of CSF from HAM/TSP patients are able to express and export Tax protein towards the CSF. This is the first report of the presence of Tax protein in cerebrospinal fluid cells and CSF from HAM/TSP HTLV-I seronegative patients.