Decreased CCR5 expression on CD4+ T cells of SIV-infected sooty mangabeys

Sooty mangabeys are the natural host of simian immunodeficiency virus (SIVsm). When injected into rhesus macaques, SIVsm infection results in progressive declines in CD4(+) T cells, opportunistic infections, and AIDS. In contrast, SIV-infected sooty mangabeys do not develop disease and live an apparently normal life span in captivity, despite maintaining high levels of virus in plasma throughout their lives. Determining the mechanisms by which sooty mangabeys have evolved to resist disease progression and AIDS may be useful in designing effective vaccine and therapeutic strategies to combat HIV-1 infection in humans. This article demonstrates that SIV-infected sooty mangabeys have significantly reduced CCR5 expression on their CD4(+) T cells compared with uninfected mangabeys or rhesus macaques. In contrast, no differences in CCR5 coexpression are found on CD8(+) T cells. Moreover, no differences in absolute numbers of CD4(+) T cells or rates of CD4(+) T cell proliferation were detected between SIV-infected and uninfected mangabeys. Combined, this suggests that either CD4(+) T cells downregulate CCR5 expression, or that CCR5(+)CD4(+) T cells are lost and not replenished in early SIV infection of sooty mangabeys. Regardless of the mechanism involved, significantly lower levels of CCR5 expression on CD4(+) T cells of SIV-infected mangabeys may play a major role in the diminished immune responses and the lack of disease progression in this natural host species.     

The effect of route of immunization on mucosal immunity and protection

In macaques, the route of immunization has a profound effect on the immune response. Augmenting rectal or vaginal immunization with oral or nasal immunization enhanced the secretory IgA, serum IgG, and T cell responses. However, targeted iliac lymph node (TILN) immunization with recombinant simian immunodeficiency virus (SIV) gp120 and p27 elicited the most consistent mucosal antibody responses in the rectum, vagina, urine, seminal fluid, and blood. Both mucosal and TILN immunization induced specific CD4+ T cell proliferative responses in the iliac lymph nodes, which drain these mucosal surfaces, and in the splenic and circulating T cells. Rectal mucosal challenge with cell-free SIV induced total protection in 4 of 7 macaques that were immunized by the TILN route, and, compared with unimmunized macaques or those immunized by the mucosal route (P<.001), it induced a >90% decrease in virus load in 3 of them. Protection from mucosal rectal infection with SIV was significantly associated with an increase in the CD8 suppressor factor (which was generated by the iliac lymph node), RANTES, and MIP-1beta (P<.01).     

Antiviral CD8+ T cells in the genital tract control viral replication and delay progression to AIDS after vaginal SIV challenge in rhesus macaques immunized with virulence attenuated SHIV 89.6

The recently failed clinical efficacy trial of an acquired immunodeficiency syndrome (AIDS) vaccine that elicits antiviral CD8⁺ T‐cell responses has emphasized the challenge of producing an effective vaccine against human immunodeficiency virus (HIV). In the simian immunodeficiency virus (SIV)/ rhesus monkey model of AIDS, live‐attenuated lentivirus ‘vaccines’ provide the best protection from uncontrolled viral replication and clinical disease after pathogenic SIV challenge. This review summarizes a recent series of studies in which we show that after vaginal SIV challenge of rhesus macaques immunized with an attenuated lentivirus protection from uncontrolled viral replication is primarily mediated by CD8⁺ T cells in the vaginal mucosa. Immunization with a chimeric simian/human immunodeficiency virus (SHIV) results in a systemic infection that induces a moderate population of SIV‐specific CD8⁺ and CD4⁺ T cells with cytolytic potential in the vaginal mucosa. Depletion of CD8⁺ T cells at the time of SIV challenge completely abrogates the protection mediated by prior infection with attenuated SHIV. Further after vaginal SIV challenge, the only significant expansion of SIV‐specific T cells occurs in the vagina in these animals. No significant expansion of T‐cell responses was observed in systemic lymphoid tissues. Thus, the presence of SIV‐specific CD8⁺ T cells in the vagina on the day of vaginal SIV challenge and a modest expansion of local effector T cells is sufficient to stop uncontrolled SIV replication. It seems that T‐cell based vaccine strategies that can elicit mucosal effector CD8⁺ T‐cell populations and avoid inducing systemic T‐cell proliferation upon exposure to HIV have the greatest potential for mimicking the success of live‐attenuated lentiviral vaccines.     

Intestinal double-positive CD4+CD8+ T cells of neonatal rhesus macaques are proliferating, activated memory cells and primary targets for SIVMAC251 infection

Peripheral blood and thymic double-positive (DP) CD4(+)CD8(+) T cells from neonates have been described earlier, but the function and immunophenotypic characteristics of other tissue-derived DP T cells are not clearly understood. Here, we demonstrate the functional and immunophenotypic characteristics of DP cells in 6 different tissues, including thymus from normal neonatal rhesus macaques (Macaca mulatta) between 0 and 21 days of age. In general, intestinal DP T cells of neonates have higher percentages of memory markers (CD28(+)CD95(+)CD45RA(low)CD62L(low)) and proliferation compared with single-positive (SP) CD4(+) and CD8(+) T cells. In addition, percentages of DP T cells increase and CD62L expression decreases as animals mature, suggesting that DP cells mature and proliferate with maturity and/or antigen exposure. Consistent with this, intestinal DP T cells in neonates express higher levels of CCR5 and are the primary targets in simian immunodeficiency virus (SIV) infection. Finally, DP T cells produce higher levels of cytokine in response to mitogen stimulation compared with SP CD4(+) or CD8(+) T cells. Collectively, these findings demonstrate that intestinal DP T cells of neonates are proliferating, activated memory cells and are likely involved in regulating immune responses, in contrast to immature DP T cells in the thymus.     

Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue.     

Hepatitis C virus-induced secretion of inflammatory chemokines preferentially recruits NKG2A+CD8+ T cells

In patients with hepatitis C, a loss-of-function mutation of chemokine receptor CCR5 (CCR5Delta32) has been shown to be associated with spontaneous viral clearance and lower levels of hepatic inflammation. In the present study, we show that CCR5 is coexpressed with the inhibitory NKG2A receptor on CD8(+) T cells. Consequently, CCR5(+) T cells were highly susceptible to NKG2A-mediated inhibition of cytotoxic activity and NKG2A(+) lymphocytes were preferentially attracted by CCR5 ligands induced by hepatitis C virus E2 antigen. Thus, CCR5 is likely to exert immunoregulatory effects in hepatitis C virus infection by preferentially recruiting CD8(+) T cells bearing the inhibitory NKG2A receptor to the liver.     

Systemic and Intestinal Viral Reservoirs in CD4+ T Cell Subsets in Primary SIV Infection

The HIV reservoir size in target CD4+ T cells during primary infection remains unknown. Here, we sorted peripheral and intestinal CD4+ T cells and quantified the levels of cell-associated SIV RNA and DNA in rhesus macaques within days of SIVmac251 inoculation. As a major target cell of HIV/SIV, CD4+ T cells in both tissues contained a large amount of SIV RNA and DNA at day 8–13 post-SIV infection, in which productive SIV RNA highly correlated with the levels of cell-associated SIV DNA. Memory CD4+ T cells had much higher viral RNA and DNA than naïve subsets, yet memory CD4+ T cells co-expressing CCR5 had no significant reservoir size compared with those that were CCR5-negative in blood and intestine. Collectively, memory CD4+ T cells appear to be the major targets for primary infection, and viral reservoirs are equally distributed in systemic and lymphoid compartments in acutely SIV-infected macaques.     

Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses

In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1- to 3-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a complete, irreversible, and systemic depletion of CD4⁺ T lymphocytes in rhesus monkeys within weeks of infection. By using small-molecule competitors specific for CCR5 and CXCR4 in ex vivo assays, we found that highly pathogenic SHIV_DH12R exclusively uses CXCR4 for infection of rhesus peripheral blood mononuclear cells, whereas SIV_mac239 and SIV_smE543 use CCR5 for entry into the same cells. During the period of peak virus production in SHIV_DH12R- or SHIV_89.6P-infected rhesus monkeys, massive elimination of CXCR4⁺ naïve CD4⁺ T cells occurred. In contrast, circulating CCR5⁺ memory CD4⁺ T cells were selectively depleted in rapidly progressing SIV-infected monkeys. At the time of their death, two SIV rapid progressors had experienced a nearly complete loss of the memory CD4⁺ T cell subset from the blood and mesenteric lymph nodes. Thus, pathogenic SHIVs and SIVs target different subsets of CD4⁺ T cells in vivo, with the pattern of CD4⁺ T lymphocyte depletion being inextricably linked to chemokine receptor use. In the context of developing an effective prophylactic vaccine, which must potently control virus replication during the primary infection, regimens that suppress SHIVs might not protect monkeys against SIV or humans against HIV-1.Highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a rapid, systemic, and complete loss of CD4⁺ T lymphocytes within weeks of inoculation of rhesus monkeys, high and sustained levels (>10⁷ copies per ml of plasma) of viral RNA, and death from immunodeficiency in 12–30 weeks (1–3). This rapid and irreversible CD4⁺ T cell-depleting phenotype is markedly different from that observed for either simian immunodeficiency virus (SIV) or HIV-1, both of which generally induce more gradual and moderate losses of CD4⁺ T cells, and much slower development of clinical disease in macaques and humans, respectively. Surprisingly, SHIVs have proven to be more controllable by the same vaccine regimens that are ineffective against SIV (4–7). Vaccine strategies that readily and durably suppress plasma SHIV RNA levels and prevent the associated global loss of CD4⁺ T lymphocytes only transiently control SIV viral load, and SIV-challenged macaques invariably succumb to AIDS after similar immunizations.The distinctive features of in vivo SHIV and SIV infections enumerated above suggest that the underlying mechanism(s) of disease induction by each virus may be different. Side-by-side comparisons of CD4⁺ T cell subsets targeted by SHIVs and SIV during infections of rhesus monkeys were therefore carried out. In the case of SIV, four (of the 10 initially inoculated) rapidly progressing animals were studied because they exhibit virological parameters and clinical symptoms that are similar to those reported for macaques infected with SHIVs (8). Ex vivo experiments, employing competitors specific for CCR5 and CXCR4, revealed that SIVs exclusively used CCR5 to enter and spread through cultured rhesus monkey peripheral blood mononuclear cells (PBMCs), whereas SHIV_DH12R used CXCR4, but not CCR5, during productive infections of the same cells. In inoculated rhesus monkeys, massive depletion of naïve CD4⁺ T lymphocytes was observed during the period of peak SHIV production (weeks 1 to 3). In contrast, memory CD4⁺ T cells were selectively eliminated from the blood and lymph nodes in rapidly progressing SIV-infected animals. The expression of CXCR4 on virtually all naïve and a significant fraction of memory CD4⁺ T lymphocytes ultimately makes both subsets the target of highly pathogenic SHIVs, and explains the rapid, irreversible, and complete depletion of CD4⁺ T cells in SHIV, but not SIV infections of macaques.     

RANTES production from CD4+ lymphocytes correlates with host genotype and rates of human immunodeficiency virus type 1 disease progression

Several chemokine and chemokine receptor parameters were measured in peripheral blood mononuclear cells obtained from patients before they became infected with human immunodeficiency virus type 1 (HIV-1). After HIV-1 infection, the parameters were compared with plasma HIV-1 RNA levels and with rates of CD4(+) lymphocyte decline. Patients who were heterozygous for the Delta32CCR5 allele had significantly higher levels of RANTES production from their CD4(+) lymphocytes than did patients who did not carry the Delta32CCR5 allele (P=.01). Higher RANTES production levels from ex vivo-activated CD4(+)-enriched lymphocytes, but not CD8(+) lymphocytes, correlated with lower plasma HIV-1 RNA levels 9-12 months after infection (P= .01) and with slower rates of CD4(+) lymphocyte decline (P= .002). CCR5 expression levels on ex vivo-activated CD4(+) lymphocytes did not correlate with markers of disease progression. These results further support the hypothesis that chemokine production levels are associated with HIV-1 replication in vivo.     

Resting naive CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques

Unlike HIV-1 and simian immunodeficiency virus (SIV), which induce a slow, unrelenting loss of immune function spanning several years, highly pathogenic simian-human immunodeficiency viruses (SHIVs) induce a rapid, complete, and irreversible depletion of CD4(+) T lymphocytes in rhesus monkeys within weeks of infection, leading to death from immunodeficiency. We recently reported that, because these SHIVs exclusively use the CXCR4 coreceptor for cell entry, they target naive CD4(+) T cells for depletion in infected monkeys, whereas SIVs, which use CCR5, not CXCR4, cause the selective loss of memory CD4(+) T lymphocytes in vivo. Here we show both by DNA PCR analyses and infectivity assays, using live sorted CD4(+) T lymphocyte subsets, that 30-90% of circulating naive cells were productively infected by day 10 after inoculation. This result implies that direct cell killing, not bystander apoptosis, is responsible for the massive loss of CD4(+) T cells in the X4-tropic SHIV model. Furthermore, we directly demonstrate that >96% of virus producing cells did not express the Ki-67 proliferation marker on day 10 after inoculation using confocal microscopic analysis of lymph nodes samples. This finding is consistent with the prodigious levels of plasma viremia measured during acute X4-tropic SHIV infections of macaques being generated almost entirely by resting naive CD4(+) T cells.     

CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques

Regulatory T (T(reg)) cells are a subset of CD25(+)CD4(+) T cells that constitutively express high levels of cytotoxic T lymphocyte antigen-4 (CTLA-4) and suppress T-cell activation and effector functions. T(reg) cells are increased in tissues of individuals infected with HIV-1 and macaques infected with simian immunodeficiency virus (SIV(mac251)). In HIV-1 infection, T(reg) cells could exert contrasting effects: they may limit viral replication by decreasing immune activation, or they may increase viral replication by suppressing virusspecific immune response. Thus, the outcome of blocking T(reg) function in HIV/SIV should be empirically tested. Here, we demonstrate that CD25(+) T cells inhibit virus-specific T-cell responses in cultured T cells from blood and lymph nodes of SIV-infected macaques. We investigated the impact of CTLA-4 blockade using the anti-CTLA-4 human antibody MDX-010 in SIV-infected macaques treated with antiretroviral therapy (ART). CTLA-4 blockade decreased expression of the tryptophan-depleting enzyme IDO and the level of the suppressive cytokine transforming growth factor-beta (TGF-beta) in tissues. CTLA-4 blockade was associated with decreased viral RNA levels in lymph nodes and an increase in the effector function of both SIV-specific CD4(+) and CD8(+) T cells. Therefore, blunting T(reg) function in macaques infected with SIV did not have detrimental virologic effects and may provide a valuable approach to complement ART and therapeutic vaccination in the treatment of HIV-1 infection.     

Cryptosporidiosis in rhesus macaques challenged during acute and chronic phases of SIV infection

The intestinal immune dysfunction due to loss of mucosal and peripheral CD4(+) T cells in individuals with HIV/AIDS is presumably responsible for the establishment of persistent cryptosporidiosis. Simian immunodeficiency virus (SIV)-infected macaques were used to investigate the phase/timing in SIV infection, which permits a self-limiting Cryptosporidium parvum infection to become persistent in immunodeficient hosts because of significant mucosal immune defects. Two groups of SIV-infected macaques were challenged with C. parvum; one was challenged during the acute SIV infection phase (2 weeks post-SIV infection) and the second was challenged during the chronic SIV phase (CD4 counts 200-500 cells/μl of blood). Samples (fecal, blood, biopsy, and necropsy) were collected at different time points after infection to correlate the progression of disease with the immune status of the animals. All seven SIV-infected macaques challenged during the acute phase of SIV infection became persistently infected and excreted oocysts for 1-4 months. However, four of the six in the chronic SIV phase became infected with cryptosporidiosis, of which one survived 2 weeks and one became naturally infected. Sequential analysis of CD4(+) in blood and intestines of coinfected macaques exhibited pronounced losses of CD4 T cells during the first 2 weeks after SIV infection, followed by transient rebound of CD4 T cells in the gut after C. parvum infection, and then a gradual loss over subsequent months. Persistent cryptosporidiosis was more consistently induced during the acute SIV phase indicating that profound viral damage to gut lymphoid tissue during the acute phase was more conducive, compared with the chronic phase, to establishing persistent cryptosporidiosis than low circulating CD4 T cells.     

Pathogenic and apathogenic courses of SIV infection are associated with distinct and characteristic regulatory patterns of G1/S and G2/M cell cycle checkpoints in CD4+ T cells

Dysregulation of both the cell cycle within the CD4(+) T cells and T cell responses is characteristic for pathogenic HIV infection in humans and experimental SIV infection in rhesus macaques. However, SIV infection in sooty mangabeys does not lead to either an AIDS-like disease or such CD4(+) T cell dysregulation. A previous study has highlighted a potential role for cell cycle regulatory proteins in these distinct clinical outcomes. This study was performed to characterize the effect of SIV infection on the expression of cell cycle-related molecules in CD4(+) T cells of rhesus macaques and sooty mangabeys in attempts to define activation-induced gene expression patterns associated with disease resistance or susceptibility. First, T cell receptor (TCR)-mediated cell activation induced gene expression profiles that were unique to CD4(+) T cells from SIV-naive sooty mangabeys and rhesus macaques. More importantly, distinct and reproducible gene expression patterns were detected in CD4(+) T cells as a result of in vivo SIV infection in animals from each of the two species. In addition, SIV infection in both species showed significant differential effects on TCR activation-induced expression with a reproducible alteration of 10 genes highlighted by discordant effects on expression of Cyclin D3, Cyclin B, and RAD17. Therefore SIV infection in rhesus macaques and sooty mangabeys exhibits distinct and reproducible effects on cell cycle regulation in CD4(+) T cells during T cell activation that may be the basis for disease susceptibility vs. resistance in these two species, respectively.     

CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain

Brain capillary endothelial cells (BCECs) are targets of CD4-independent infection by HIV-1 and simian immunodeficiency virus (SIV) strains in vitro and in vivo. Infection of BCECs may provide a portal of entry for the virus into the central nervous system and could disrupt blood–brain barrier function, contributing to the development of AIDS dementia. We found that rhesus macaque BCECs express chemokine receptors involved in HIV and SIV entry including CCR5, CCR3, CXCR4, and STRL33, but not CCR2b, GPR1, or GPR15. Infection of BCECs by the neurovirulent strain SIV/17E-Fr was completely inhibited by aminooxypentane regulation upon activation, normal T cell expression and secretion in the presence or absence of ligands, but not by eotaxin or antibodies to CD4. We found that the envelope (env) proteins from SIV/17E-Fr and several additional SIV strains mediated cell–cell fusion and virus infection with CD4-negative, CCR5-positive cells. In contrast, fusion with cells expressing the coreceptors STRL33, GPR1, and GPR15 was CD4-dependent. These results show that CCR5 can serve as a primary receptor for SIV in BCECs and suggest a possible CD4-independent mechanism for blood–brain barrier disruption and viral entry into the central nervous system.     

Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2

We measured apoptosis of subsets of T lymphocytes by single-cell analysis of caspase activation, to confirm high turnover of chemokine receptor CCR5(+) T cells in subjects with acute, primary human immunodeficiency virus type 1 (HIV-1) infection (PHI). High levels of spontaneous apoptosis, consisting mainly of CD8(+) T lymphocytes, were closely associated with increases in the activation markers Ki-67, CD38, and the HIV coreceptor CCR5 and with decreases in Bcl-2 and the interleukin (IL)-7 receptor at the single-cell level. Increased expression of Ki-67 and CCR5 ex vivo, as well as increased apoptosis, was seen in all T cell receptor beta-chain variable region (TCRBV) subfamilies studied. The addition of IL-2 or IL-15, but not IL-7, significantly inhibited caspase activation, increased Bcl-2 expression, and rapidly initiated proliferation in vitro of CD8(+) T cells expressing CCR5 and multiple TCRBV subfamilies. Furthermore, IL-15 receptor alpha-chain messenger RNA levels were increased in peripheral blood mononuclear cells during PHI. These results suggest that CCR5(+)Ki-67(+)Bcl-2(dim) activated T cells generated during PHI traffic via blood to tissue sites, where the cells may survive and/or further proliferate under the local influence of IL-2 or IL-15. Understanding cytokine effects on CCR5(+) T cells will be important in understanding chronic HIV-1 replication and pathogenesis.     

Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

Certain chemokine receptors serve as cofactors for HIV type 1 envelope (env)-mediated cell–cell fusion and virus infection of CD4-positive cells. Macrophage tropic (M-tropic) HIV-1 isolates use CCR5, and T cell tropic (T-tropic) strains use CXCR4. To investigate the cofactors used by simian immunodeficiency viruses (SIV), we tested four T-tropic and two M-tropic SIV env proteins for their ability to mediate cell–cell fusion with cells expressing CD4 and either human or nonhuman primate chemokine receptors. Unlike HIV-1, both M- and T-tropic SIV envs used CCR5 but not CXCR4 or the other chemokine receptors tested. However, by testing a panel of CCR5/CCR2b chimeras, we found that the structural requirements for CCR5 utilization by M-tropic and T-tropic SIV strains were different. T-tropic SIV strains required the second extracellular loop of CCR5 whereas a closely related M-tropic SIV strain could, like M-tropic HIV-1 strains, use the amino-terminal domain of CCR5. As few as two amino acid changes in the SIV env V3 domain affected the regions of CCR5 that were critical for fusogenic activity. Receptor signaling was not required for either fusion or infection. Our results suggest that viral tropism may be influenced not only by the coreceptors used by a given virus strain but also by how a given coreceptor is used.     

Differential effect of methotrexate on the increased CCR2 density on circulating CD4 T lymphocytes and monocytes in active chronic rheumatoid arthritis, with a down regulation only on monocytes in responders

OBJECTIVES: To evaluate the effect of orally administered methotrexate (MTX) on the density of CC chemokine receptor 2 (CCR2) and CXC chemokine receptor 3 (CXCR3) on circulating monocytes, and the coexpression of CXCR3 and CCR2 on CD4 T lymphocytes in patients with active chronic rheumatoid arthritis. METHODS: All 34 patients with rheumatoid arthritis fulfilled the 1987 American Rheumatism Association criteria and were followed for 16 weeks after starting MTX. Peripheral blood mononuclear cells were analysed for CCR2 and CXCR3 density by three-colour flow cytometry before initiation of MTX and at week 12. RESULTS: 22 (65%) patients were non-responders, 12 (35%) patients responded to MTX by American College of Rheumatology (ACR)20% criteria, and 8 (24%) of these patients responded by ACR50%. In patients with active rheumatoid arthritis before starting MTX, CCR2 density on circulating monocytes, CD4(+) CXCR3(+) and CD4(+) CXCR3(-) T lymphocytes was increased compared with controls. During 12 weeks of MTX treatment, the CCR2 density on monocytes decreased significantly in the ACR50% group but not in the ACR20% and non-responder groups. The increased CCR2 density on CD4(+) CXCR3(+) and CD4(+) CXCR3(-) T lymphocytes was unaffected by the reduction in disease activity measured in relation to MTX treatment. The percentage of both monocytes and CD4(+) CXCR3(+) and CD4+ CXCR3(-) T lymphocytes among the peripheral circulating mononuclear cells did not change during MTX treatment. CONCLUSIONS: Active chronic rheumatoid arthritis is characterised by enhanced CCR2 density on circulating monocytes and CD4(+) CXCR3(+) and CD4(+) CXCR3(-) T lymphocytes. During MTX treatment, a decrease in CCR2 density on monocytes in the ACR50% responder group was associated with decreased disease activity. The increased CCR2 density on CD4(+) CXCR3(+) and CD4(+) CXCR3(-) T lymphocytes was uninfluenced by MTX and disease activity.     

Human T cell leukemia virus type 1 up-regulation after simian immunodeficiency virus-1 coinfection in the nonhuman primate

The effects that human T cell leukemia virus (HTLV) type 1 and simian immunodeficiency virus (SIV) coinfection have on HTLV-1 dynamics and disease progression were tested in a nonhuman primate model. Seven rhesus macaques were experimentally inoculated with HTLV-1, and a persistent infection was established. Coinfection with SIV/smB670 resulted in increased HTLV-1 p19 antigens in peripheral blood mononuclear cells and HTLV-1 proviral loads. Circulating CD2(+) and CD8(+) T lymphocytes increased over preinoculation levels, along with a progressive decrease in CD4(+) T cells, typical for terminal SIV disease. Finally documented was the striking emergence of up to 19% of HTLV-associated "flower cell" lymphocytes in the circulation, as seen in patients with adult T cell leukemia/lymphoma. CD8(+)CD25(+) T cell subpopulation increases were positively correlated with flower cell appearance and suggested their possible role in this process. We conclude that SIV may have the potential to up-regulate HTLV-1 and disease expression.