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Influence of Human T Cell Lymphotropic Virus Type 2 Coinfection on Virological and Immunological Parameters in HIV Type 1–Infected Patients

  1. Sylvina Bassani1,
  2. Mariola Lopez1,
  3. Carlos Toro1,
  4. Victoria Jimenez1,
  5. Josá M. Sempere2,
  6. Vincent Soriano1, and
  7. Jose M. Benito1
  1. 11Service of Infectious Diseases, Hospital Carlos III, Madrid
  2. 2Biotechnology Department, University of Alicante, Alicante, Spain
  1. Reprints or correspondence: Dr. Josá Miguel Benito, Service of Infectious Diseases, Hospital Carlos III, Madrid 28029, Spain(jbenito1{at}hotmail.com).
 
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Abstract

Background. Human T cell lymphotropic virus type 2 (HTLV-2) infection is not rare among injection drug users with human immunodeficiency virus (HIV) infection and may exert a protective role in the progression of HIV disease.

Methods. Immunological and virological parameters were compared in HIV–HTLV-2—coinfected patients and a control group of HIV-monoinfected subjects. All individuals were antiretroviral therapy naive. HIV-specific CD8+ T cell levels were measured using an interferon-γ assay in response to 125 optimally defined HIV peptides divided into 5 pools. Immune activation was evaluated by measuring levels of CD38 in different CD4+ and CD8+ T cell subsets. In a subgroup of patients, the production of CCL4 in parallel with interferon-γ was assessed in response to Gag peptides.

Results. Lower plasma HIV-RNA levels were found in HIV–HTLV-2—coinfected patients than in HIV-monoinfected patients, despite the 2 groups having similar CD4+ T cell counts. Coinfected patients also had significantly lower levels of CD38 expression in total CD8+ T cells and in its naive subset. CD8+ T cell levels specific for each pool of peptides were similar in both groups, but cells mainly contributing to HIV Gag—specific responses in coinfected patients were CCL4 positive and interferon-γ negative, whereas for HIV-monoinfected subjects, the response was dominated by CCL4-positive and interferon-γ—positive cells.

Conclusions. HTLV-2 coinfection may exert a protective role on HIV disease progression by lowering HIV replication and immune activation. A predominance of CCL4 single positive HIV-specific CD8+ T cells in HIV–HTLV-2—coinfected patients could explain this effect.

Human T cell lymphotropic virus (HTLV) types 1 (HTLV-1) and 2 (HTLV-2) were the first retroviruses identified in humans (in 1980 and 1982, respectively) [1]. HTLV-2 is closely related to HTLV-1, with which it shares a tropism for T lymphocytes [2] and similar mechanisms of transmission. Human disease is linked to HTLV-1 with the development of adult T cell leukemia and tropical spastic paraparesis. In contrast, HTLV-2 infection has not been clearly associated with human disease, although sporadic cases of neurologic and lymphoproliferative disorders have been reported in HTLV-2 carriers, including injection drug users who are coinfected with HIV-1 [3–5].

Interactions between HIV-1 and HTLV-1/2 have been reported. Both viruses share transmission routes, and coinfections are not rare. An accelerated course of HIV-1 infection has been reported in men who have sex with men who are coinfected with HIV-1 and HTLV-1 [6]. This finding of increased HIV pathogenicity is supported by data from in vitro studies, which have shown that HTLV-1 tax gene products enhance the release of infectious HIV-1 particles [7]. In contrast, slower CD4+ T cell depletion has been reported for subjects coinfected with HIV-1 and HTLV-2 [8–10]. Several explanations have been proposed that could account for this potential protective effect of HTLV-2 on the pathogenesis of HIV disease. First, the different cellular tropism of HTLV-2 with respect to HTLV-1, meaning that the former preferentially infects CD8+ T lymphocytes, and the latter preferentially infects CD4+ T cells, as does HIV-1 [11]. Second, HTLV-2 tax protein may have an immunomodulatory effect, increasing the synthesis of IFN-γ by HTLV-2—infected cells [12]. Finally, HTLV-2 could exert a protective effect on the progression of HIV disease by inducing the production of the chemokines CCL3, CCL4, and CCL5. Casoli et al. [9] have shown that HTLV-2—infected CD8+ T cells may inhibit HIV replication in CD4+ T lymphocytes and that this effect is mediated by chemokines produced by CD8+ T cells. Moreover, Lewis et al. [13] have demonstrated that CD8+ T lymphocytes recovered from HTLV-2—infected patients spontaneously produce high levels of chemokines. These molecules are the natural ligands for CCR5, the main coreceptor for HIV-1 entry into the cells, and they suppress infection with macrophage tropic HIV-1 strains [14, 15]. Individuals who have been exposed to HIV-1 yet remain uninfected produce high levels of these chemokines in vivo [16]. In long-term HIV infection, however, the role of these molecules on the natural course of the disease is somewhat controversial. An association between enhanced chemokine production and a slow progression of HIV disease [17, 18], as well as between enhanced chemokine production and a lower HIV load [19], has been reported, although other studies have not confirmed these findings [20].

To further investigate the potential mechanisms that could determine a slow progression of HIV infection in patients coinfected with HTLV-2, we compared levels of HIV replication, immune activation, HIV-specific CD8+ T lymphocyte responses and production of CCL4 in patients with HIV–HTLV-2 coinfection and in HIV-monoinfected individuals.

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Patients and Methods

Study population. All drug-naive HIV-infected individuals who visited an HIV reference clinic located in Madrid, Spain, in 2003 were examined for the presence of HTLV-1/2 antibodies. PBMCs were obtained from all HTLV-1/2—positive subjects and from a control group of matched individuals and were cryopreserved. Specimens were stored in liquid nitrogen until the moment of the analysis. The viability of thawed PBMCs was always >85%.

Diagnosis of HTLV-2 infection. Plasma specimens obtained from all subjects were screened for antibodies to HTLV using a commercial ELISA (Murex HTLV-I+II; Abbott). All specimens with repeated ELISA reactivity were further examined using a Western blot assay (BioBlot HTLV; Biokit), which is able to distinguish HTLV-1 and HTLV-2 antibodies. A positive result for either HTLV-1 or HTLV-2 was determined in accordance with the HTLV European Research Network criteria [21].

Immune activation levels. CD38 expression was differentially examined on the surface of CD4+CD45RO+, CD8+CD45RO+, CD4+CD45RO-, and CD8+CD45RO- T cells using a modified commercial quantitative flow cytometry assay (Cellquant CD38/CD8-PE; Biocytex). Two 25-µL aliquots of whole blood were incubated with anti-CD38 Mab or with a negative isotypic control. A 25-µL aliquot of calibrated bead suspension was incubated with the negative isotypic control. Samples were incubated for 10 min at room temperature; then, polyclonal anti-mouse IgG-FITC was added to all samples, which were incubated for another 10 min. Specimens were then incubated with a neutralization solution for 10 min. Then, anti–CD4-ECD, anti–CD45RO-PE (Coulter), and anti–CD8-PCY5 (Vitro-Imico) were used for counter-staining all samples, except for the calibrated beads. RBCs were lysed using the Coulter lysing solution, washed once using a washing buffer, and resuspended with the same buffer before performing the cytometric analysis.

HIV peptides. A total of 125 optimally defined HIV-specific CD8+ T lymphocyte epitopes 9–11 amino acids in length were synthesized as free acids of >98% purity (Peptide Synthesis Facility, Autonomous University; Barcelona, Spain). Five different pools of HIV peptides were made according to their origin: Gag (45 peptides), Pol (27 peptides), Env (26 peptides), Nef (21 peptides), and other regulatory proteins (Reg; 5 peptides). Lyophilized peptides were resuspended in DMSO (Sigma), mixed into the different pools, aliquoted, and stored at -80°C. The concentration of each individual peptide in the different pools was 1 mg/mL, and the final concentration in the cultures was 10 µg/mL.

HIV-specific cytotoxic CD8+ T lymphocyte measurement. A half-million PBMCs were incubated with each pool of peptides at a concentration of 10 µg/mL for each individual peptide, with 0.5 µg each of CD28 and CD49d monoclonal antibodies (to provide exogenous costimulation), for 6 h at 37°C in 250 µL of RPMI/10% fetal calf serum (R10). The secretion inhibitor Brefeldin A was added to the cultures during the second hour of incubation. Control conditions included stimulation with medium alone as a negative control and stimulation with phorbol myristate acetate (PMA; 50 ng/mL) plus ionomycin (1 µmol/L) as a positive control. After incubation, cells were harvested and washed with PBS/1% BSA. A commercial kit was used to permeabilize cells (Cytofix/Cytoperm Plus; Pharmingen). Permeabilized cells were then incubated with anti–CD8-PECy5 and anti–CD69-PE (Vitro-Imico), anti–CD3-ECD (Beckmann-Coulter), and anti–IFN-γ-FITC (Pharmingen). Gating was done on CD8bright cells, a minimum of 20,000 of which were used. The percentage of CD3+CD8+CD69+ T cells that expressed IFN-γ was assessed using each individual's negative control to establish quadrant boundaries. A level of 0.05% CD3+CD8+ cells expressing IFN-γ and CD69 (after background substraction) was considered to be the threshold for considering the response to be positive.

CCL4 production. In 7 individuals coinfected with HTLV-2 and HIV, as well as in 10 HIV-monoinfected subjects, the production of both CCL4 and IFN-γ was examined in response to HIV Gag peptides. The same protocol used for measurement of CD8+ T lymphocyte levels was also used here, although a different panel of monoclonal antibodies was employed, including anti–IFN-γ-FITC, anti–CCL4-PE (BD Biosciences Pharmingen), anti–CD3-ECD (Beckmann-Coulter), and anti–CD8-Pcy5 (Vitro-Imico).

Statistical analyses. Differences between groups were assessed using Student's t test. Associations between variables were explored using the χ2 test for qualitative variables and the Pearson or Spearman ρ correlation coefficients for quantitative parameters. Mean values are shown with SDs. Statistical significance was defined as P<; .05. All statistical analyses were performed using the SPSS software, version 9.0 (SPSS).

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Results

Twenty-five (4.5%) of the 550 tested HIV-infected individuals were found to be coinfected with HTLV-2. No cases of HIV and HTLV-1 coinfection were reported. Thirty HIV-monoinfected individuals were chosen as control subjects. All patients were naive for antiretroviral drugs and were former injection drug users. Distribution of male and female subjects was similar in both groups (80% and 90% of coinfected and monoinfected subjects, respectively, were male), as was also true for mean age (38 ± 6 and 35 ± 7 years, respectively).

CD4+ T cell counts and plasma HIV-RNA levels. Mean CD4+ T cell counts were similar in HIV–HTLV-2—coinfected patients and HIV-monoinfected patients (513 ± 55 vs. 523 ± 53 cells/µL). Plasma HIV-RNA levels, however, were significantly lower in HIV–HTLV-2—coinfected individuals than in HIV-monoinfected individuals (3.34 ± 0.24 vs. 4.08 ± 0.2 log copies/mL; P = .03).

T cell activation. CD38 expression was quantitatively analyzed to evaluate the level of activation in naive and memory subsets of CD4+ and CD8+ T cells. CD38 expression was higher in all T lymphocyte subsets recovered from HIV-monoinfected subjects than in those recovered from HIV–HTLV-2—coinfected individuals, with statistically significant differences for total CD8+ T cells and naive CD8+ T cells (total CD8+ cells, 4964 ± 875 vs. 2910 ± 590 CD38 molecules/cell [P<; .05]; naive CD8+ cells, 5024 ± 919 vs. 2589 ± 540 CD38 molecules/cell [P<; .05]; memory CD8+ cells, 4753 ± 787 vs. 3630 ± 848 CD38 molecules/cell; total CD4+ cells, 3348 ± 468 vs. 2351 ± 214 CD38 molecules/cell; naive CD4+ cells, 3517 ± 523 vs. 2667 ± 262 CD38 molecules/cell; and memory CD4+ cells, 2889 ± 487 vs. 2123 ± 324 CD38 molecules/cell) ( figure 1). Among the whole study population, as well as among each group of patients separately, there was a positive correlation between plasma HIV RNA level and the level of T cell activation, with the highest correlation seen for CD8+ memory T cells (Pearson ρ, 0.67; P<; .001).

Figure 1
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Figure 1

Levels of CD38 expression on different T cell subsets in HIV-monoinfected patients (hatched bars) and HIV—human T cell lymphotropic virus type 2—coinfected patients (black bars).

HIV-1—specific CD8+ T lymphocyte responses. Figure 2 shows 2 representative flow cytometry analyses: one for an HIV–HTLV-2—coinfected subject and the other for an HIV-monoinfected patient. CD8+ T lymphocyte levels (defined as the percentage of CD8+ T cells producing IFN-γ and expressing the early activation marker CD69) specific for each of the 5 different pools tested were similar in HIV-monoinfected and HIV–HTLV-2—coinfected patients ( figure 3). The rate of total HIV-specific responses (defined as the sum of the partial responses to each pool) was 2.3% ± 0.5% versus 2.4% ± 0.6% of total CD8+ T cells for HIV-monoinfected and HIV–HTLV-2—coinfected patients, respectively. Moreover, the contribution of each pool to the total CD8+ T lymphocyte response was similar in both groups, with the Gag peptide pool the one yielding the highest level of response (0.9% ± 0.2% and 1.1% ± 0.3% in monoinfected and coinfected patients, respectively).

Figure 2
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Figure 2

IFN-γ production by CD8+ T cells in response to the HIV Gag, Pol, Env, Nef, and Reg pool of peptides in 1 HIV—human T cell lymphotropic virus type 2—coinfected patient (upper plots) and 1 HIV-monoinfected patient (lower plots).

Figure 3
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Figure 3

Level of HIV-specific CD8+ responses against different HIV peptide pools in HIV-monoinfected patients (hatched bars) and HIV—human T cell lymphotropic virus type 2—coinfected patients (black bars).

CCL4 production. The production of CCL4 and IFN-γ in response to polyclonal stimulation (PMA plus ionomycin) and to HIV Gag peptides was assessed in 7 individuals coinfected with HTLV-2 and HIV-1 and in 10 HIV-monoinfected subjects. Figure 4 shows 2 representative examples of flow cytometry results in 1 coinfected patient and 1 monoinfected patient. On the basis of CCL4 and IFN-γ production, 3 different CD8+ T cell subsets were defined: single CCL4-positive cells, single IFN-γ—positive cells, and double CCL4-positive/IFN-γ—positive cells. In response to polyclonal stimulation, most CD8+ T cells produced both cytokines, with no significant difference in the levels for HIV–HTLV-2—coinfected patients versus HIV-monoinfected patients ( figure 5).

Figure 4
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Figure 4

IFN-γ and macrophage inflammatory protein (MIP)–1β production by CD8+ T cells in response to polyclonal stimulation (left plots) and to a HIV Gag pool of peptides (right plots) in 1 HIV—human T cell lymphotropic virus type 2—coinfected patient (upper plots) and 1 HIV-monoinfected patient (lower plots).

Figure 5
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Figure 5

Levels of macrophage inflammatory protein (MIP)–1β and IFN-γ production by CD8+ T cells in response to polyclonal stimulation (left graph) and to stimulation with HIV Gag peptides (right graph) in HIV-monoinfected patients (hatched bars) and HIV—human T cell lymphotropic virus type 2—coinfected patients (black bars). +, Positive; -, negative.

The response to HIV Gag peptides was first analyzed considering the total responses, defined as the sum of the 3 different subsets of CD8+ T cells (IFN-γ—positive/CCL4-positive, IFN-γ—positive/CCL4-negative, and IFN-γ—negative/CCL4-positive cells). Responses were slightly higher in HIV-monoinfected patients than in HIV–HTLV-2—coinfected patients, but the differences did not reach statistical significance (4.5% ± 2.4% and 3.1% ± 3.7% CD8+ T cells for monoinfected and coinfected patients, respectively). When examining the levels of the 3 different subsets separately, IFN-γ—positive/ CCL4-positive double-positive cells were significantly increased in HIV-monoinfected patients, whereas the other 2 subsets were equally represented in both groups of patients ( figure 5). Finally, the contribution of the 3 different subsets to the total Gag-specific response was analyzed. Figure 6 shows the proportion of the total response for each subset. In HIV-monoinfected individuals, this response was mainly dominated by double-positive cells (52% of the total response), whereas in coinfected patients, it was largely mediated by CCL4+/IFN-γ—negative/CD8+ T cells (60% of the total response).

Figure 6
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Figure 6

Profile of HIV Gag—specific CD8+ responses in HIV-monoinfected and HIV—human T cell lymphotropic virus type 2—coinfected patients, based on the representation of 3 different subsets: IFN-γ—positive/macrophage inflammatory protein (MIP)–1β—positive CD8+ T cells (black), IFN-γ—positive/MIP-1β—negative CD8+ T cells (dots), and IFN-γ—negative /MIP-1β—positive CD8+ T cells (stripes).

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Conclusions

Dual infection with HIV-1 and HTLV-2 is found with relatively high frequency among injection drug users in western Europe and North America [22, 23]. Each virus influences the pathogenesis and natural history of the other. HIV-associated immunosuppression may induce the development of HTLV-2—associated illnesses, such as peripheral neuropathy and non-Hodgkin lymphoma [24, 25]. The influence of HTLV-2 on HIV disease progression is more controversial, but most studies have suggested a protective effect [8, 9, 13]. Our results add a further piece of information in line with this beneficial influence of HTLV-2 on the progression of HIV disease. Coinfected individuals have significantly lower plasma HIV RNA levels than do HIV-monoinfected subjects, despite having similar CD4+ T cell counts. Coinfected patients also have significantly lower levels of T cell activation, and this is especially recognizable when measuring CD38 on CD8+ T cells. This lower level of activation most likely reflects the lower rate of HIV replication seen in coinfected patients, compared with HIV-monoinfected subjects, because these 2 parameters are strongly and positively correlated, in agreement with prior reports [26, 27]. On the basis of these observations, slower HIV disease progression should be expected in HIV–HTLV-2—coinfected patients, because T cell activation is one of the main mechanisms driving CD4+ T cell depletion in HIV-infected persons [28, 29].

Different mechanisms have been proposed to explain the beneficial effect of HTLV-2 on HIV pathogenesis. The Tax protein of HTLV-2 might have an immunomodulatory effect, increasing the synthesis and release of IFN-γ by HTLV-2—infected cells [12]. However, in our study we found similar levels of IFN-γ production in response to a polyclonal stimulus (PMA plus ionomycin) in HIV-monoinfected and HIV–HTLV-2—coinfected patients. Moreover, the production of IFN-γ in response to HIV peptide pools did not differ in both groups of patients. Casoli et al. [9] have suggested that HTLV-2 could exert a protective effect on HIV disease progression, by inducing the production of chemokines CCL3, CCL4, and CCL5. These chemokines are the natural ligands for CCR5, the main coreceptor used by HIV to enter into its target cells and in vitro studies have demonstrated that HIV infection is suppressed in the presence of these chemokines [14]. In our study, we did not find different levels of CCL4 when comparing HIV-monoinfected and HIV–HTLV-2—coinfected patients, either in response to polyclonal stimulus or in response to specific HIV peptides. However, HIV Gag—specific responses were dominated by single CCL4-producing CD8+ T cells in HIV–HTLV-2—coinfected patients, whereas in HIV-monoinfected individuals, this subset of CD8+ T cells only represented a small proportion of the total Gag-specific responses. In this way, we can hypothesize that single CCL4-producing CD8+ T cells could play an important role suppressing HIV replication. Because of the relatively small size of our study population, we could not further establish a significant association between plasma HIV RNA level and levels of single CCL4-producing CD8+ T cells.

In summary, our study supports the hypothesis of a protective effect of HTLV-2 on the progression of HIV disease. This beneficial effect seems to operate through a reduction in HIV replication. HIV-specific CD8+ T cell responses mediated by CCL4-positive/IFN-γ—negative cells could be involved in this phenomenon. Further studies examining larger populations are needed to confirm this hypothesis.

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Acknowledgements

Financial support. Fundación para la Investigación y la Prevención del SIDA en España (project 36483/05), Fundación Investigación y Educación en SIDA, Red de Investigación en SIDA (project Redes no. 173), Agencia Lain Entralgo, and Comunidad Autónoma de Madrid.

Potential conflicts of interest. All authors: no conflicts.

  • Received July 12, 2006.
  • Accepted August 29, 2006.
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References

  1. ↵
    1. Salemi M,
    2. Van Dooren S,
    3. Vandamme A
    . Origin and evolution of Human and Simian T-cell lymphotropic viruses. AIDS Rev 1999;1:131-9.
  2. ↵
    1. Gallo R
    . Human retroviruses after 20 years: a perspective from the past and prospects their future control. Immunol Rev 2002;185:236-65.
    CrossRefMedlineWeb of Science
  3. ↵
    1. Soriano V,
    2. Gutierrez M,
    3. Bravo R,
    4. Diaz F,
    5. Olivan J,
    6. Gonzalez-Lahoz J
    . Severe myopathy in an injection drug user coinfected with HIV type 1 and human T cell leukemia virus type II. Clin Infect Dis 1994;19:350-1.
    FREE Full Text
    1. Dooneief G,
    2. Marlink R,
    3. Bell K,
    4. et al
    . Neurologic consequences of HTLV-II infection in injection-drug users. Neurology 1996;46:1556-60.
    Abstract/FREE Full Text
  5. ↵
    1. Zehender G,
    2. Colasante C,
    3. Santambrogio S,
    4. et al
    . Increased risk of developing peripheral neuropathy in patients coinfected with HIV-1 and HTLV-2. J Acquir Immune Defic Syndr 2002;31:440-7.
    MedlineWeb of Science
  6. ↵
    1. Bartholomew C,
    2. Blattner W,
    3. Cheghorn F
    . Progression to AIDS in homosexual men co-infected with HIV and HTLV-I in Trinidad. Lancet 1987;2:1469.
    MedlineWeb of Science
  7. ↵
    1. Zack J,
    2. Cann A,
    3. Lugo J,
    4. Chen IS
    . HIV-1 production from peripheral blood cells after HTLV-I induced mitogenic stimulation. Science 1988;240:1026-9.
    Abstract/FREE Full Text
  8. ↵
    1. Magnani G,
    2. Elia G,
    3. Casoli C
    . HTLV type II infection among high risk groups and its influence on HIV-1 disease progression. Eur J Epidemiol 1995;11:527-32.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Casoli C,
    2. Vicenzi E,
    3. Cimarelli A,
    4. et al
    . HTLV-2 down regulates HIV-1 replication in IL-2 stimulated primary PBMC of coinfected individuals trough expression of MIP-1-alpha. Blood 2000;95:2760-9.
    Abstract/FREE Full Text
  10. ↵
    1. Cimarelli A,
    2. Duclos C,
    3. Gessain A,
    4. et al
    . Quantification of HTLV-II proviral copies by competitive polymerase chain reaction in peripheral blood mononuclear cells of Italian injecting drug users, central Africans and Amerindians. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10:198-207.
    MedlineWeb of Science
  11. ↵
    1. Casoli C,
    2. Cimarelli A,
    3. Bertazzoni U
    . Cellular tropism on human T-cell leukaemia virus type II enlarged to B lymphocytes in patients with high proviral load. Virology 1995;206:1126-32.
    CrossRefMedlineWeb of Science
  12. ↵
    1. Bovolenta C,
    2. Pilotti E,
    3. Mauri M,
    4. et al
    . HTLV type 2 induces survival and proliferation of CD34(+) TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-gamma and granulocyte macrophage-colony-stimulating factor. Blood 2002;99:224-31.
    Abstract/FREE Full Text
  13. ↵
    1. Lewis M,
    2. Gautier V,
    3. Wang X,
    4. Kaplan M,
    5. Hall W
    . Spontaneous production of cc-chemokines by individuals infected with HTLV-II alone and HTLV-II/HIV-1 coinfected individuals. J Immunol 2000;165:4127-32.
    Abstract/FREE Full Text
  14. ↵
    1. Dragic T,
    2. Litwin G,
    3. Alway S,
    4. et al
    . HIV-1 entry into CD4+ cells is mediated by the chemokines receptor CC-CKR-5. Nature 1996;381:667-70.
    CrossRefMedline
  15. ↵
    1. Connor R,
    2. Sheridan C,
    3. Ceradini S,
    4. Choe S,
    5. Landau N
    . Changes in coreceptor usage correlates with disease progression in HIV-1 infected individuals. J Exp Med 1997;185:621-6.
    Abstract/FREE Full Text
  16. ↵
    1. Paxton W,
    2. Martin D,
    3. Tse T,
    4. et al
    . Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nat Med 1996;2:412-6.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Ullum H,
    2. Cozzi LA,
    3. Victor J,
    4. et al
    . Production of β-chemokines in HIV infection: evidence that high levels of macrophage inflammatory protein-1β are associated with a decreased risk of HIV disease progression. J Infect Dis 1998;177:331-6.
    Abstract/FREE Full Text
  18. ↵
    1. Cocchi F,
    2. De Vico AL,
    3. Yarchoan R,
    4. et al
    . Higher macrophage inflammatory protein (MIP)-1α and MIP-1β levels from CD8+ T cells are associated with asymptomatic HIV infection. Proc Natl Acad Sci U S A 2000;97:13812-7.
    Abstract/FREE Full Text
  19. ↵
    1. Ferbas J,
    2. Giorgi JV,
    3. Amini S,
    4. et al
    . Antigen-specific production of RANTES, macrophage inflammatory protein (MIP)-1α, and MIP-1β in vitro is a correlate of reduced HIV burden in vivo. J Infect Dis 2000;182:1247-50.
    Abstract/FREE Full Text
  20. ↵
    1. Jennes W,
    2. Sawadogo S,
    3. Koblavi-Deme S,
    4. et al
    . Positive association between β-chemokine producing T cells and HIV type 1 viral load in HIV-infected subjects in Abidjan, Cote d'Ivoire. AIDS Res Hum Retroviruses 2002;18:171-7.
    CrossRefMedlineWeb of Science
  21. ↵
    The HTLV European Research Network. Seroepidemiology of the human T-cell leukaemia/lymphoma viruses in Europe. J Acquir Immune Defic Syndr 1996;13:68-77.
    Web of Science
  22. ↵
    1. Khabbaz R,
    2. Onorato I,
    3. Cannon R,
    4. et al
    . Seroprevalence of HTLV-1 and HTLV-2 among intravenous drug users and persons in clinics for sexually transmitted diseases. N Engl J Med 1992;326:375-80.
    MedlineWeb of Science
  23. ↵
    1. Page J,
    2. Lai S,
    3. Chitwood D,
    4. Klimas N,
    5. Smith P,
    6. Fletcher M
    . HTLV-I/II seropositivity and death from AIDS among HIV-1 seropositive intravenous drug users. Lancet 1990;335:1439-41.
    CrossRefMedlineWeb of Science
  24. ↵
    1. Zehender G,
    2. De Magdalena C,
    3. Osio M,
    4. et al
    . High prevalence of HTLV-II infection in patients affected by HIV type 1-associated predominantly sensory polyneuropathy. J Infect Dis 1995;172:1595-8.
    Abstract/FREE Full Text
  25. ↵
    1. Zehender G,
    2. Meroni L,
    3. Piconi S,
    4. et al
    . Frequent detection of antibodies against HTLV antigens in patients with AIDS-related non-Hodgkin lymphoma. AIDS Res Hum Retroviruses 1995;11:823-7.
    MedlineWeb of Science
  26. ↵
    1. Orendi J,
    2. Bloem A,
    3. Borleffs J,
    4. et al
    . Activation and cell cycle antigens in CD4+ and CD8+ T cells correlate with plasma HIV-1 RNA level in HIV-1 infection. J Infect Dis 1998;178:1279-87.
    Abstract/FREE Full Text
  27. ↵
    1. Benito JM,
    2. Lopez M,
    3. Lozano S,
    4. Martinez P,
    5. González-Lahoz J,
    6. Soriano V
    . CD38 expression on CD8+ T lymphocytes as a marker of residual virus replication in chronically HIV-infected patients receiving antiretroviral therapy. AIDS Res Hum Retroviruses 2004;20:227-33.
    CrossRefMedlineWeb of Science
  28. ↵
    1. Gougeon M,
    2. Lecoeur H,
    3. Dulioust A,
    4. Enouf MG,
    5. Crouvoiser M,
    6. Goujard C
    . Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J Immunol 1996;156:3509-20.
    Abstract
  29. ↵
    1. Bofill M,
    2. Mocroft A,
    3. Lipman M,
    4. Medina E,
    5. Borthwick NJ,
    6. Sabin CA
    . Increased numbers of primed activated CD8+CD45RO+ T cells predict the decline of CD4+ T cells in HIV-infected patients. AIDS 1996;10:827-34.
    MedlineWeb of Science
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  1. Clin Infect Dis. (2007) 44 (1): 105-110. doi: 10.1086/510076
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