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Expression of Chemokine Receptors CCR5 and CXCR4 on CD4+ T Cells and Plasma Chemokine Levels During Treatment of Active Tuberculosis in HIV-1-Coinfected Patients
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JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 39(3) 1 July 2005
Wolday, Dawit MD, PhD*; Tegbaru, Belete MSc*; Kassu, Afework MSc*; Messele, Tsehaynesh PhD*; Coutinho, Roel MD, PhD; van Baarle, Debbie PhD; Miedema, Frank PhD
From the *Ethio-Netherlands AIDS Research Project (ENARP) and Ethiopian Health and Nutrition Research Institute (EHNRI), Addis Ababa, Ethiopia; Municipal Health Services, Amsterdam, The Netherlands; and Sanquin Research and Landstiener Laboratory of Academic Medical Center, Amsterdam, The Netherlands.
Summary:
The pathogenesis of persistently elevated plasma HIV viremia in patients coinfected with tuberculosis (TB) during anti-TB treatment in Africans remains unknown.
We examined the expression of chemokine receptors CCR5 and CXCR4 on CD4+ T cells and plasma chemokine levels of macrophage inflammatory protein (MIP)-1, MIP-1, regulated on activation normal T expressed and secreted (RANTES), and stromal cell-derived factor (SDF)-1 among TB patients with HIV coinfection during the first 2 months of anti-TB treatment.
During treatment of TB, the plasma HIV-1 load and CD4+ T-cell count remained unchanged. Levels of CCR5 and CXCR4 expression on CD4+ T cells as well as plasma levels of chemokines remained persistently elevated during anti-TB treatment.
Persistently elevated plasma HIV viremia also paralleled persistently elevated expressions of activated CCR5+ or CXCR4+ CD4+ T cells. These results suggest that increased expression of CCR5 and CXCR4 on an activated CD4+ T-cell population coupled with persistently elevated chemokines may provide a suitable condition for continuous replication of HIV associated with TB coinfection. This, in turn, may contribute, at least in part, to the observed persistently elevated plasma HIV viremia in coinfected patients despite anti-TB treatment.
ARTICLE TEXT
HIV-infected patients are at increased risk of developing active Mycobacterium tuberculosis (MTB) disease from reactivated latent infection or exogenous infection, and active MTB in HIV-infected patients has been shown to accelerate HIV disease progression.1-3
The immune background profile of individuals living in sub-Saharan Africa is characterized by chronic activation.4-7 In this respect, increased susceptibility to de novo infection with HIV and/or accelerated HIV disease progression in individuals from sub-Saharan Africa might be attributable to the chronic and persistent immune activation by ongoing immune responses to various endemic infections that prevail on the continent.7 It is worth noting that in patients with tuberculosis (TB), there is evidence of immune activation.8-11 In addition, the level of immune activation of peripheral monocytes from patients with active pulmonary TB is sufficient to enhance susceptibility to productive infection with HIV in vitro,12 and MTB (and its antigens) can upregulate HIV replication in vitro.10,13-17 In HIV-infected patients, mycobacteria also seem to augment HIV replication as measured in the peripheral circulation,10 lung,15,17-19 and lymphoid tissues,20,21 through mechanisms involving immune activation.10,21 It is interesting to note that increased expression of CCR5 and/or CXCR4, major chemokine HIV coreceptors, as well as their chemokine ligands, has been demonstrated in human monocyte-derived macrophages, alveolar macrophages, and CD4+ T cells in the course of in vivo and in vitro MTB infection,16,19,21-23 and the expression of these coreceptors seems to depend on the state of activation of the cells.24-26 Although the lung could be a preferential organ for HIV replication during active TB,15,17-19 it is worth noting that a significant increase (as high as 3- to 160-fold) in plasma HIV viremia has been observed during the acute phase of MTB disease,10,27 possibly related to mycobacteremia, which is frequently observed in HIV-coinfected patients.28 Indeed, CD4+ T cells, the principal target for HIV,29,30 contribute to more than 95% of the total virus production.31 In contrast to what has been observed in MTB disease in the Western world, where plasma HIV viremia often declines after successful TB treatment,10 few studies have shown that the HIV viral load remains unchanged during or after completion of successful anti-TB treatment in Africans.11,27,32,33 The pathogenesis of the persistently elevated plasma HIV viremia in patients coinfected with TB in Africa remains undefined, although several studies have suggested a role of the persistently activated immune system.11,33
In the present study, therefore, we studied the expression of chemokine receptors CCR5 and CXCR4 on CD4+ T cells and plasma chemokine levels of macrophage inflammatory protein (MIP)-1, MIP-1, regulated on activation normal T expressed and secreted (RANTES), and stromal cell-derived factor (SDF)-1 among TB patients with or without HIV coinfection during the first 2 months of anti-TB treatment. Our findings indicate that the persistently increased expression of chemokine receptors and chemokines may provide a potential mechanism of increased replication of HIV and may contribute to the persistence of HIV viremia observed in Africans despite anti-TB treatment.
DISCUSSION
In this study, we noted that during anti-TB treatment, there was no significant increase in CD4 cell count among the TB/HIV-coinfected patients compared with patients who were not coinfected with HIV. These findings are similar to those reported by Morris et al.33 Poor CD4 T-cell restoration during TB treatment may be the consequence of uncontrolled HIV-1 replication.
In addition to the CD4 molecule,29,30 the chemokine receptors CCR5 and CXCR4 have been identified as major requisites for HIV-1 entry into CD4+ T cells and macrophages.35-38 The -chemokine receptor CCR5 is the most important coreceptor used by macrophage (M)-tropic viruses, whereas the -chemokine receptor CXCR4 is the dominant coreceptor for T-cell line (T)-tropic viruses.35-39 The expression pattern of the chemokine receptors on various cells is believed to have an influence on susceptibility, viral tropism, and HIV disease progression.39,40 It is interesting to note that there is ample evidence for immune activation in the course of active MTB disease.8-11 In addition, the expression of these receptors has been shown to be dependent on the state of activation of the target cells.24-26
Previous studies have demonstrated that there was an increase in CCR5 expression on mononuclear cells in the lung16,19 and lymphoid tissue21 from HIV patients coinfected with mycobacteria. CD4+ T cells latently infected with HIV are a major source of circulating viremia.31 Because mycobacteremia is also frequent in HIV-infected patients28 and MTB-derived antigens have been shown to induce chemokine receptor expression on immune cells in vitro16,22,23 and chemokines,16 we undertook the present study to evaluate the impact of anti-TB treatment in TB/HIV-coinfected persons. This study demonstrates that CCR5- and CXCR4-expressing CD4+ T cells were elevated in TB patients also coinfected with HIV. The findings from the present study concur with those reported previously.16,23 In the present study, in addition, we have shown that activated CD4+ T cells express high levels of CCR5 and CXCR4 and that the expression of the coreceptors and cellular activation paralleled each other. Susceptibility to infection with HIV is associated with levels of CCR5 expression,25,41 and MTB can activate CD4+ T cells to induce HIV replication.10 Thus, increased expression of chemokine receptors within the CD4+ T-cell subpopulation may, at least in part, explain the mechanistic pathway of increased HIV replication observed during coinfection with TB. In addition, dysregulation in the chemokines might play an important role in this process.
We have previously demonstrated that acute MTB infection is associated with significant increases in plasma HIV viremia.32 The plasma HIV load remained persistently elevated during anti-TB treatment, however. The data are consistent with those from prior studies in Africa of plasma HIV viremia during MTB disease,11,27,33 but differ from those of an earlier report10 that successful treatment of MTB in Western subjects is associated with a significant reduction in HIV-1 RNA levels. Lawn et al11 demonstrated that sustained plasma HIV viremia is associated with persistently elevated concentrations of tumor necrosis factor- (TNF) during anti-TB treatment. Morris et al33 also recently showed that the sustained plasma HIV-1 load during anti-TB treatment was associated with persistently elevated HLA-DR and CD38 in a CD8+ T-cell population. In the present study, we observed that the levels of CCR5 and CXCR4 expressed on CD4+ T cells remained persistently elevated and paralleled the level of cellular activation as well as chemokines during anti-TB treatment. The fact that plasma viremia declines after successful treatment of infections other than TB42-44 but remains persistently elevated during coinfection with TB indicates that TB-induced immune activation remains protracted and suggests that TB infection might modulate HIV-1-specific immune responses, which are not restored once TB is successfully treated. A similar observation has been noted in treated schistosomiasis patients coinfected with HIV in Uganda.45 One could argue that the absence of change in CD4 cell count, HIV viral load, and chemokine receptors and chemokines could be the result of ineffective anti-TB treatment. Only those patients infected with a sensitive M. tuberculosis isolate were included in this specific study, however.46
In Ethiopia, the predominant circulating HIV virus is subtype C.47-49 Although CXCR4 use by HIV-1 isolates often evolves during disease progression associated with the emergence of syncytium-inducing variants,50 this is not the case from our studies in Ethiopia.49 Indeed, in advanced HIV disease, CCR5 use by non-syncytium-inducing isolates was the predominant phenomenon observed, and the emergence of syncytium-inducing viruses that use CXCR4 was found to be rare for subtype C viruses.49,51 Moreover, Morris et al52 showed that R5 HIV-1 subtype C variants are preferentially recovered from patients with active TB. Taken together, the data suggest that increased expression of CCR5 on an activated CD4+ T-cell population may provide the availability of target cells for increased replication of HIV associated with TB coinfection.
These studies suggest that expression of chemokine receptors in the course of TB along with other components of the immune activation process may provide a background for more efficient availability of target cells for enhanced replication of HIV, and hence accelerated HIV disease progression, in coinfected individuals as well as increased susceptibility of TB positive/HIV negative patients after exposure to HIV-1. Although the introduction of highly active antiretroviral therapy (HAART) may alter the sequela of increased HIV replication in the course of MTB disease, in much of the developing world, where both HIV and TB prevail, the findings underscore the need for concomitant antiretroviral treatment with anti-TB treatment or an intensive first 2 months of anti-TB treatment followed by antiretroviral therapy. Moreover, more effective strategies for treatment of latent TB infection should be provided for HIV-coinfected persons.
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