Diagnostic accuracy of a rapid E1-antigen test for chikungunya virus infection in a reference setting.

OBJECTIVES: Rapid diagnostic tests targeting virus-specific antigen could significantly enhance the diagnostic capacity for chikungunya virus infections. We evaluated the accuracy of an immunochromatographic antigen test for diagnosis of chikungunya in a reference laboratory for arboviruses. METHODS: An immunochromatographic rapid test that uses mouse monoclonal antibodies as a tracer against the E1-envelope protein of chikungunya (ARKRAY, Inc. Kyoto, Japan) was evaluated. Sensitivity was tested in sera from travellers with RT-PCR confirmed chikungunya virus infection (Eastern/Central/Southern African (ECSA) genotype) (n=9) and from patients diagnosed during the 2014-2015 chikungunya outbreak on Aruba (Asian genotype, n=30). Samples from patients with other febrile and non-febrile illnesses (n=26), sera spiked with Flavivirus and Alphavirus reference strains (n=13, including non-spiked serum), and samples containing other selected pathogens (n=20) were used to test specificity of the E1-antigen test. RESULTS: Sensitivity of the E1-antigen test was 8/9 (88.9%, 95% CI 56.5-98.0) for the ECSA genotype, but only 10/30 (33.3%, 95% CI 19.2-51.2) for the Asian genotype. Overall diagnostic specificity was 49/59 (83.1%, 95% CI 71.5-90.5). CONCLUSIONS: The E1-antigen test we evaluated had fair diagnostic sensitivity for ECSA genotype chikungunya, but low sensitivity for Asian genotype, and poor overall specificity. Antibodies that react across genotypes will be required for further development of a rapid test for chikungunya. Performance of new tests should be evaluated against different chikungunya genotypes.

Nodes-and-connections RNAi knockdown screening: identification of a signaling molecule network involved in fulvestrant action and breast cancer prognosis.

Although RNA interference (RNAi) knockdown screening of cancer cell cultures is an effective approach to predict drug targets or therapeutic/prognostic biomarkers, interactions among identified targets often remain obscure. Here, we introduce the nodes-and-connections RNAi knockdown screening that generates a map of target interactions through systematic iterations of in silico prediction of targets and their experimental validation. An initial RNAi knockdown screening of MCF-7 human breast cancer cells targeting 6560 proteins identified four signaling molecules required for their fulvestrant-induced apoptosis. Signaling molecules physically or functionally interacting with these four primary node targets were computationally predicted and experimentally validated, resulting in identification of four second-generation nodes. Three rounds of further iterations of the prediction-validation cycle generated third, fourth and fifth generation of nodes, completing a 19-node interaction map that contained three predicted nodes but without experimental validation because of technical limitations. The interaction map involved all three members of the death-associated protein kinases (DAPKs) as well as their upstream and downstream signaling molecules (calmodulins and myosin light chain kinases), suggesting that DAPKs play critical roles in the cytocidal action of fulvestrant. The in silico Kaplan-Meier analysis of previously reported human breast cancer cohorts demonstrated significant prognostic predictive power for five of the experimentally validated nodes and for three of the prediction-only nodes. Immunohistochemical studies on the expression of 10 nodal proteins in human breast cancer tissues not only supported their prognostic prediction power but also provided statistically significant evidence of their synchronized expression, implying functional interactions among these nodal proteins. Thus, the Nodes-and-Connections approach to RNAi knockdown screening yields biologically meaningful outcomes by taking advantage of the existing knowledge of the physical and functional interactions between the predicted target genes. The resulting interaction maps provide useful information on signaling pathways cooperatively involved in clinically important features of the malignant cells, such as drug resistance.

ERalpha-CITED1 co-regulated genes expressed during pubertal mammary gland development: implications for breast cancer prognosis.

Expression microarray analysis identified over 930 genes regulated during puberty in the mouse mammary gland. Most prominent were genes whose expression increased in parallel with pubertal development and remained high thereafter. Members of the Wnt, transforming growth factor-beta and oestrogen-signalling pathways were significantly overrepresented. Comparison to expression data from CITED1 knockout mice identified a subset of oestrogen-responsive genes displaying altered expression in the absence of CITED1. Included in this subset are stanniocalcin2 (Stc2) and amphiregulin (Areg). Chromatin immunoprecipitation revealed that ERalpha binds to oestrogen response elements in both the Stc2 and Areg genes in the mammary gland during puberty. Additionally, CITED1 and ERalpha localize to the same epithelial cells of the pubertal mammary gland, supporting a role for interaction of these two proteins during normal development. In a human breast cancer data set, expression of Stc2, Areg and CITED1 parallel that of ERalpha. Similar to ERalpha, CITED1 expression correlates with good outcome in breast cancer, implying that potential maintenance of the ERalpha-CITED1 co-regulated signalling pathway in breast tumours can indicate good prognosis.

CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis.

Expression microarray analysis identified CITED1 among a group of genes specifically upregulated in the pubertal mouse mammary gland. At puberty, CITED1 localizes to the luminal epithelial cell population of the mammary ducts and the body cells of the terminal end buds. Generation of CITED1 gene knockout mice showed that homozygous null mutants exhibit retarded mammary ductal growth at puberty and, in addition, dilated ductal structures with a lack of spatial restriction of the subtending branches. Analysis of CITED1 homozygous null and heterozygous null mammary gland gene expression using microarrays suggested that the mammary-specific phenotype seen in the homozygous null females is due to a disturbance in the transcription of a number of key mediators of pubertal ductal morphogenesis. These include estrogen and TGFbeta responsive genes, such as the EGFR/ErbB2 ligand, amphiregulin, whose transcription we suggest is directly or indirectly regulated by CITED1.

Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein.

CITED1, a CBP/p300-binding nuclear protein that does not bind directly to DNA, is a transcriptional coregulator. Here, we show evidence that CITED1 functions as a selective coactivator for estrogen-dependent transcription. When transfected, CITED1 enhanced transcriptional activation by the ligand-binding/AF2 domain of both estrogen receptor-alpha (ERalpha) and ERbeta in an estrogen-dependent manner, but it affected transcriptional activities of other nuclear receptors only marginally. CITED1 bound directly to ERalpha in an estrogen-dependent manner through its transactivating domain, and this binding activity was separable from its p300-binding activity. CITED1 was strongly expressed in nulliparous mouse mammary epithelial cells and, when expressed in ER-positive MCF-7 breast cancer cells by transduction, exogenous CITED1 enhanced sensitivity of MCF-7 cells to estrogen, stabilizing the estrogen-dependent interaction between p300 and ERalpha. The estrogen-induced expression of the transforming growth factor-alpha (TGF-alpha) mRNA transcript was enhanced in the CITED1-expressing MCF-7 cells, whereas estrogen-induced expression of the mRNA transcripts for progesterone receptor or pS2 was not affected. Chromatin immunoprecipitation assay revealed that endogenous CITED1 is recruited to the chromosomal TGF-alpha promoter in MCF-7 cells in an estrogen-dependent manner but not to the pS2 promoter. These results suggest that CITED1 may play roles in regulation of estrogen sensitivity in a gene-specific manner.

Over-expression of MSG1 transcriptional co-activator increases melanin in B16 melanoma cells: a possible role for MSG1 in melanogenesis.

MSG1 is a 27 kDa nuclear protein that is expressed strongly in melanotic B16 melanoma cells but very weakly in amelanotic B16 cells. Transient expression of B16 cells with an expression vector for MSG1 resulted in an increase in levels of the enzyme dopachrome tautomerase but not tyrosinase, as detected by western blotting. Stable transfection of B16 melanoma cells with plasmids containing the full length MSG1 or its deletion mutants, however, generated cell lines that showed an increase in levels of tyrosinase, dopachrome tautomerase and cellular melanin when compared with control transfected cells. Our results suggest that MSG1 plays an important role in melanogenesis, by regulating the levels of the enzymes of the pigmentary system via tyrosinase and dopachrome tautomerase.

Quintuple deglycosylation mutant of simian immunodeficiency virus SIVmac239 in rhesus macaques: robust primary replication, tightly contained chronic infection, and elicitation of potent immunity against the parental wild-type strain.

We previously generated a mutant of simian immunodeficiency virus (SIV) lacking 5 of a total of 22 N-glycans in its external envelope protein gp120 with no impairment in viral replication capability and infectivity in tissue culture cells. Here, we infected rhesus macaques with this mutant and found that it also replicated robustly in the acute phase but was tightly, though not completely, contained in the chronic phase. Thus, a critical requirement for the N-glycans for the full extent of chronic infection was demonstrated. No evidence indicating reversion to a wild type was obtained during the observation period of more than 40 weeks. Monkeys infected with the mutant were found to tolerate a challenge infection with wild-type SIV very well. Analyses of host responses following challenge revealed no neutralizing antibodies against the challenge virus but strong secondary responses of cytotoxic T lymphocytes against multiple antigens, including Gag-Pol, Nef, and Env. Thus, the quintuple deglycosylation mutant appeared to represent a novel class of SIV live attenuated vaccine.

Aberrant expression of MSG1 transcriptional activator in human malignant melanoma in vivo.

MSG1 was originally isolated as a candidate pigmentation-related gene. MSG1 mRNA transcripts were expressed strongly in cultured human and mouse normal epidermal melanocytes, and in highly pigmented mouse melanoma cells, while its expression was very weak in cultured non-pigmented human melanoma cells. Thus, MSG1 was initially proposed to be a melanocyte-specific gene, and its possible role in pigmentation has been speculated. It was found recently that the MSG1 protein interacts functionally with Smad4, which plays a pivotal role in signal transduction of transforming growth factor-beta. In this study, we analyzed MSG1 protein expression by immunohistochemistry using human tumor samples from nevus and malignant melanoma to reveal its role in pigmentation and melanoma development in vivo. A relatively strong but heterogeneous expression of MSG1 protein was seen in melanomas compared with weak expression in nevi. In nevi, MSG1 expression was mostly confined to the pigmented region, while it was expressed in both pigmented and non-pigmented regions in melanoma. Intracellularly, MSG1 protein was localized in the cytoplasm of nevus cells, but was seen in both nuclei and cytoplasm of melanoma cells. These results support a hypothesis that MSG1 plays a role in pigmentation. It is also suggested that MSG1 may be involved in malignant transformation of pigment cells. Alternatively, the aberrant expression of MSG1 in melanoma cells might be due to the abnormal environment, including aberrant cytokine or growth factor expression, associated with melanoma formation.

Effect of certain chemicals on the reproduction of medaka (Oryzias latipes).

In order to understand the effects of estrogenic chemicals on fish reproduction, we exposed male medaka (Oryzias latipes) to a natural estrogen [17 beta-estradiol (17 beta-E2)] and three estrogenic chemicals [bisphenol-A, nonylphenol (NP) and di(2-ethylhexyl)phthalate (DEHP)]. After two weeks' exposure, one male medaka was kept together with two female medaka for spawning, and the number of eggs and hatchings were compared to those of a negative control group. The results indicated that exposure to 17 beta-E2 caused a significant decrease in the number of eggs and hatchings as compared to the negative control group at and above 3 nmol/l. Also, the highest concentrations of bisphenol-A and NP caused a decrease in the number of hatchings, but no decrease in hatchings was observed in DEHP treatments. In the treatment using these chemicals the decrease in egg numbers was not so much as in hatching numbers. When compared to other in vitro studies, concentrations observed to have adverse effects on reproduction in this study are generally lower. In addition, it was suggested that physical alterations, such as an induction of plasma vitellogenin, were caused at much lower concentrations than those at which a decline in reproductivity was actually induced.

The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain.

Transforming growth factor-beta (TGF-beta) family members signal through a unique set of intracellular proteins called Smads. Smad4, previously identified as the tumor suppressor DPC4, is functionally distinct among the Smad family, and is required for the assembly and transcriptional activation of diverse, Smad-DNA complexes. We previously identified a 48-amino acid proline-rich regulatory element within the middle linker domain of this molecule, the Smad4 activation domain (SAD), which is essential for mediating these signaling activities. We now characterize the functional activity of the SAD. Mutants lacking the SAD are still able to form complexes with other Smad family members and associated transcription factors, but cannot activate transcription in these complexes. Furthermore, the SAD itself is able to activate transcription in heterologous reporter assays, identifying it as a proline-rich transcriptional activation domain, and indicating that the SAD is both necessary and sufficient to activate Smad-dependent transcriptional responses. We show that transcriptional activation by the SAD is p300-dependent, and demonstrate that this activity is associated with a physical interaction of the SAD with the amino terminus of p300. These data identify a novel function of the middle linker region of Smad4, and define the role of the SAD as an important locus determining the transcriptional activation of the Smad complex.

Sendai virus gene start signals are not equivalent in reinitiation capacity: moderation at the fusion protein gene.

In paramyxovirus transcription, viral RNA polymerase synthesizes each monocistronic mRNA by recognizing the gene start (S) and end (E) signals flanking each gene. These signal sequences are well conserved in the virus family; nevertheless, they do exhibit some variations even within a virus species. In Sendai virus (SeV) Z strain, the E signals are identical for all six genes but there are four (N, P/M/HN, F, and L) different S signals with one or two nucleotide variations. The significance of these variations for in vitro and in vivo replication has been unknown. We addressed this issue by SeV reverse genetics. The luciferase gene was placed between the N and P gene so that recombinant SeVs expressed luciferase under the control of each of the four different S signals. The S signal for the F gene was found to drive a lower level of transcription than that of the other three, which exhibited comparable reinitiation capacities. The polar attenuation of SeV transcription thus appeared to be not linear but biphasic. Then, a mutant SeV whose F gene S signal was replaced with that used for the P, M, and HN genes was created, and its replication capability was examined. The mutant produced a larger amount of F protein and downstream gene-encoded proteins and replicated faster than wild-type SeV in cultured cells and in embryonated eggs. Compared with the wild type, the mutant virus also replicated faster in mice and was more virulent, requiring a dose 20 times lower to kill 50% of mice. On the other hand, the unique F start sequence as well as the other start sequences are perfectly conserved in all SeV isolates sequenced to date, including highly virulent fresh isolates as well as egg-adapted strains, with a virulence several magnitudes lower than that of the fresh isolates. This moderation of transcription at the F gene may therefore be relevant to viral fitness in nature.

Enhanced anti-HIV-1 activity of CC-chemokine LD78beta, a non-allelic variant of MIP-1alpha/LD78alpha.

We compared the anti-HIV-1 activity of CC-chemokine LD78beta with that of MIP-1alpha, another CC-chemokine which shows 94% sequence homology with LD78beta. Despite its close similarity to MIP-1alpha, the anti-HIV-1 activity of LD78beta appeared to be nearly 10 times higher than that of MIP-1alpha. Mutagenesis of MIP-1alpha showed that the N-terminal additional tetrapeptide, which was present in LD78beta and absent in MIP-1alpha, is responsible for enhanced anti-HIV-1 activity. The N-terminal structure-function relationship of LD78beta described here will be of value in understanding the chemokine-receptor interactions and designing anti-HIV-1 compounds based on LD78beta.

Active HIV-1 redistribution and replication in the brain with HIV encephalitis.

The central nervous system (CNS) is of particular importance in human immunodeficiency virus type 1 (HIV-1) infection. First, the CNS may be difficult to access for anti-retroviral treatment and may become a sanctuary for residual viruses. Second, HIV-1 infection may lead to AIDS dementia complex (ADC) culminating in HIV-1 encephalitis. In order to examine the pattern of drug resistance and the role of encephalitis in enhancing viral redistribution to the CNS, we compared pol gene quasispecies of the spleen and brain in two patients with and two patients without HIV-1 encephalitis, who had been treated with zidovudine (AZT). Although a variable degree of AZT resistance was noted in both the spleen and brain of all patients, phylogenetic analysis indicated that quasispecies developed rather independently in the systemic circulation (spleen) and CNS (brain) of patients without HIV-1 encephalitis, while similar pol gene sequences were obtained from the two compartments of patients with HIV-1 encephalitis. env gene V3 region of patients with HIV-1 encephalitis showed distinct quasispecies in the spleen and brain. Our results suggest that HIV-1 redistribution to CNS is more active in cases with encephalitis and that HIV-1 distributed late to CNS grow actively under certain selective pressure exerted on the V3 region of the env gene.

Measles virus attenuation associated with transcriptional impediment and a few amino acid changes in the polymerase and accessory proteins.

Measles virus (MV) isolated in B95a cells, a marmoset B-cell line, retains full pathogenicity for cynomolgus monkeys, while its derivative obtained by adaptation to the growth in Vero cells, a monkey kidney cell line, loses the pathogenic potential (F. Kobune, H. Sakata, and A. Sugiura, J. Virol. 64:700-705, 1990). Here, we show with a pair of strains, a fresh isolate (9301B) in B95a cells and its Vero cell-adapted form (9301V), that the in vivo attenuation parallels the decrease of replication and syncytium-inducing capabilities in the original B95a cells and that these in vitro phenotypes are attributable to impediment of transcription, which is already obvious at the level of primary transcription catalyzed by the virion-associated RNA polymerase. On the other hand, cell fusion assays detected no functional difference between the glycoproteins of the two viruses. Essentially the same transcriptional impediment with reduced syncytium induction following Vero cell adaptation was found with two other pairs of strains that had been similarly prepared. Nucleotide sequence comparison between the 9301B and 9301V viruses revealed that a few (at most five) amino acid changes, which sporadically took place in the polymerase (L and P proteins) and/or accessory V and C proteins, were responsible for the in vitro and in vivo attenuation through adaptation to growth in Vero cells.

Location-specific, unequal contribution of the N glycans in simian immunodeficiency virus gp120 to viral infectivity and removal of multiple glycans without disturbing infectivity.

One of the striking features of human immunodeficiency virus, simian immunodeficiency virus (SIV), and other lentiviruses is extensive N glycosylation of the envelope protein. To assess the requirement of each N glycan for viral infectivity, we individually silenced all 23 N glycosylation sites in the gp120 subunit of SIVmac239 envelope protein by mutagenizing the canonical Asn-Xaa-Thr/Ser N glycosylation motif in an infectious molecular clone, attempted to rescue viruses from the clones, and compared the replication capability of the rescued viruses in MT4 cells. The mutation resulted in either the recovery of a fully infectious virus (category I); recovery of a faster-replicating virus, compared with the parental virus (category II); or no virus recovery (category III). These categorically different sites were not distributed randomly but were clustered. The sites of category I were localized largely in the N-terminal half, whereas the sites of categories II and III were localized in the C-terminal region, including the CD4 binding site, and the central part, including the C loop, respectively. To learn how far SIV can tolerate the removal of glycans, multiplex mutagenesis was also attempted. When they were appreciably distant from one another in the primary sequence, up to five sites could be silenced in combination without disturbing infectivity. On the other hand, it was difficult to silence contiguous sites. Thus, it appeared that a certain degree of sugar chain density over the local region had to be preserved. We discuss the potential utility of these variously deglycosylated mutants for clarifying the role of N glycans in SIV replication in vivo, as well as in the host response, and for designing vaccines and the generation of glycoprotein crystals.

MSG1 (melanocyte-specific gene 1): mapping to chromosome Xq13.1, genomic organization, and promoter analysis.

MSG1 (melanocyte-specific gene 1) is a recently isolated gene predominantly expressed in cultured normal melanocytes and pigmented melanoma cells. MSG1 encodes a 27-kDa nuclear protein that has strong intrinsic transcriptional transactivating activity. In this report, the human MSG1 gene was mapped to chromosome Xq13.1 using X chromosome-specific somatic cell hybrids, and the mouse Msg1 gene was mapped 1.9 +/- 1.3 cM proximal to Xist using an interspecific backcross panel. Both the human and the mouse MSG1 genes consist of three exons and two introns within 5 kb of genomic DNA, and their genomic structures are highly conserved. Southern blot analysis suggests the existence of MSG1 homologues in chicken, zebrafish, and Drosophila. A 2.0-kb fragment of the 5'-flanking region of the mouse Msg1 gene contains a TATA box and potential binding sites for several transcription factors including USF, Brn-3, Brn-2, TFE3, Oct-1, AP-2, and Spl. This promoter fragment activates transcription of a reporter gene in pigmented melanoma cells, but not in amelanotic melanoma cells or nonmelanocytic cells, indicating that Msg1 expression is at least partially regulated at the transcriptional level.

Negative regulation of the anti-human immunodeficiency virus and chemotactic activity of human stromal cell-derived factor 1alpha by CD26/dipeptidyl peptidase IV.

Stromal cell-derived factor 1alpha (SDF-1alpha) is a chemokine that has been shown to prevent infection of T-tropic HIV strains and is a possible substrate of CD26/dipeptidyl peptidase IV (DPPIV). In this study, we show that SDF-1alpha was cleaved at the N-terminal region by CD26/DPPIV and as a result the inhibitory activity of SDF-1alpha against HIV infection disappeared. Moreover, the chemotactic activity of SDF-1alpha also disappeared specifically by DPPIV activity of recombinant soluble CD26. These results suggested that dissemination of T-tropic HIV strains in vivo may be facilitated by CD26/DPPIV via inactivation of functional SDF-1alpha.

Regulation of expression of MSG1 melanocyte-specific nuclear protein in human melanocytes and melanoma cells.

MSG1 is a nuclear protein and a possible transcriptional transactivator that is expressed strongly in melanocytes but very weakly, if at all, in most nonmelanocytic cells or adult mouse tissues. This strong expression of MSG1 in cultured normal human epidermal melanocytes was found to be dependent on both endothelin-1 and FGF-2. The phorbol ester TPA could be substituted for endothelin-1. The MSG1 mRNA transcripts were rapidly induced by either endothelin-1 or TPA. However, FGF-2 had no effects at the mRNA level, suggesting its contribution at the translational and/or posttranslational level(s). MSG1 (as well as its mRNA transcripts) was induced by TPA in human melanoma cells, which produce FGF-2 as an autocrine growth factor. Melanoma cells derived from primary tumors or tyrosinase-positive metastatic melanoma cells expressed MSG1 after TPA treatment, while tyrosinase-negative metastatic melanoma cells or nonmelanocytic cells did not. This TPA-induced MSG1 expression in melanoma cells correlated with the expression of the MSG1 mRNA transcripts and TPA-dependent transcriptional activation of the MSG1 promoter sequence, indicating its transcriptional regulation. In vivo, MSG1 protein was detected in human nevocytic nevus confined to the pigmented region, while MSG1 expression showed cell-level heterogeneity in pigmented melanoma tissues. These results demonstrate that MSG1 expression is regulated transcriptionally and posttranscriptionally by local growth factors as well as by the cellular status of differentiation.

Dissociation of ligand-induced internalization of CXCR-4 from its co-receptor activity for HIV-1 Env-mediated membrane fusion.

The C-terminal cytoplasmic tail of chemokine receptors is important for their internalization upon ligand binding. We generated several deletion mutants of the C-terminal cytoplasmic tail of CXCR-4, a co-receptor for T cell line tropic strains of human immunodeficiency virus type 1 (HIV-1), to know whether or not co-receptor internalization is associated with HIV-1 entry. Our data showed that the removal of C-terminal 15 amino acid residues of the cytoplasmic tail from CXCR-4 completely abolished its internalization, but did not affect the co-receptor activity at all. Co-receptor activity was fully retained even when all 45 amino acid residues in the C-terminal cytoplasmic tail had been deleted. These data indicated that no cytoplasmic tail nor internalization of CXCR-4 is required for its co-receptor activity for HIV-1 entry.

Anti-HIV-1 and chemotactic activities of human stromal cell-derived factor 1alpha (SDF-1alpha) and SDF-1beta are abolished by CD26/dipeptidyl peptidase IV-mediated cleavage.

CD26 is a leukocyte-activation antigen that is expressed on T lymphocytes and macrophages and possesses dipeptidyl peptidase IV (DPPIV) activity, whose natural substrates have not been identified yet. CXC chemokines, stromal cell-derived factor 1alpha (SDF-1alpha) and 1beta (SDF-1beta), sharing the receptor CXCR-4, are highly efficacious chemoattractants for resting lymphocytes and CD34(+) progenitor cells, and they efficiently block the CXCR-4-mediated entry into cells of T cell line tropic strains of HIV type 1 (HIV-1). Here we show that both the chemotactic and antiviral activities of these chemokines are abrogated by DPPIV-mediated specific removal of the N-terminal dipeptide, not only when the chemokines are produced in transformed mouse L cell line to express human CD26 but also when they were exposed to a human T cell line (H9) physiologically expressing CD26. Mutagenesis of SDF-1alpha confirmed the critical requirement of the N-terminal dipeptide for its chemotactic and antiviral activities. These data suggest that CD26-mediated cleavage of SDF-1alpha and SDF-1beta likely occurs in human bodies and promotes HIV-1 replication and disease progression. They may also explain why memory function of CD4(+) cells is preferentially lost in HIV-1 infection. Furthermore, CD26 would modulate various other biological processes in which SDF-1alpha and SDF-1beta are involved.