| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 AIDS Virus Research Unit, National Institute for Communicable Diseases, and Department of Virology, University of the Witwatersrand, Private Bag X4, Sandringham, Johannesburg 2131, South Africa
2 Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa
3 Gertrude H. Sergievsky Centre, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA
Correspondence
Caroline T. Tiemessen
carolinet{at}nicd.ac.za
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
), a chemokine receptor utilized by R5 human immunodeficiency virus type 1 (HIV-1) in addition to CD4 for entry into leukocytes (Deng et al., 1996; Dragic et al., 1996). Aside from their role in chemotaxis, the CC chemokines are also involved in regulation of cell-mediated immunity (Matsukawa et al., 2000). The fact that the CC chemokines could block macrophage-tropic HIV-1 viruses from replicating in vitro (Cocchi et al., 1995) raised the possibility that these molecules may contribute to protective immunity against HIV-1 in vivo. Supporting this hypothesis were prototype HIV-1 vaccine studies in rhesus macaques, showing production of CC chemokines by CD8 T cells to be associated with protective immunity (Heeney et al., 1998; Lehner et al., 1996). Wasik et al. (1999) demonstrated an overexpression of CCL3, CCL4 and CCL5 in a small number of exposed–uninfected infants and suggested that these may mediate non-cytolytic inhibition of infection during perinatal HIV-1 transmission. Antiviral chemokines produced by activated leukocytes in HIV-1 exposed–uninfected individuals may play a role in establishing relative resistance to HIV-1 infection, as observed in persons who remain uninfected despite multiple high-risk sexual exposures (Paxton et al., 1996; Zagury et al., 1998).
Naturally occurring host genetic variants of chemokine and chemokine-receptor genes have further shown the important role of these molecules in altering the host immune response to HIV-1 (reviewed by O'Brien & Nelson, 2004). Recently, variation in copy number of CC chemokine ligand 3-like 1 (CCL3-L1) genes was shown to be associated with host risk of HIV-1 infection and disease progression (Gonzalez et al., 2005). However, no human prospective study has demonstrated directly that a deficient phenotype of limited production of one or more of the CC chemokines is associated with risk of acquiring HIV-1 infection.
The context of mother-to-child transmission of HIV-1 provides an ideal model in which to test potential mechanisms associated with host protective immunity to HIV-1. Measuring immune responses at birth among uninfected infants allows the distinction to be made between those infants who escape infection and those who succumb to infection. We questioned whether fetal CC chemokine production was associated with protection against HIV-1 transmission due to viral exposure at delivery and observed that infants with deficiencies in production of CCL3 were more likely to acquire HIV-1 infection. CCL3-L1 gene copy number only partially explains this phenotype, suggesting that infants who acquire infection may harbour some non-functional copies of this gene. Our findings support the hypothesis that this chemokine in particular plays an important role in protective immunity among HIV-1 exposed–uninfected infants.
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
). Women who had either received no prenatal care or who received prenatal care at community clinics where HIV testing and access to antiretroviral drugs were unavailable were eligible for this trial and were tested for HIV after delivery. Their infants were randomized to receive either nevirapine or zidovudine as prophylaxis, started within 24 h of birth. In addition to cord-blood collection, corresponding infant blood samples were also collected at birth, 6 weeks and 3 months of age to determine infection outcome by HIV-1 DNA PCR. All 6-week samples were tested first and, if found to be negative, it was assumed that the infant was uninfected. The 6-week samples that tested positive were further analysed by testing the birth sample to distinguish between intrauterine and intrapartum infection. Confirmation of intrapartum infection was obtained by testing the 3-month samples of infants who were HIV-1 DNA PCR-positive at 6 weeks, but negative at birth. From the 124 mother–child pairs from whom samples were collected, we selected for testing all infants who became infected with HIV-1 [13 were infected intrapartum (IP) and four were infected in utero (IU); one infected infant was excluded because sample preparation was inadequate for this analysis] and a random sample of uninfected children born to HIV-1-infected mothers [43 exposed–uninfected (EU)] by using a nested case–control design. The clinical characteristics of the HIV-1-infected mothers and their infants are shown in Table 1. A further 20 cord-blood samples from infants born to HIV-1-uninfected mothers at the same site were collected to serve as negative controls.
|
) to yield a total of 46 transmitting and 74 non-transmitting mother–child pairs. Written informed consent was obtained from all study participants and the study was approved by the Institutional Review Boards of the investigators.
Isolation of cord-blood mononuclear cells (CBMCs).
CBMCs and peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation on Histopaque Ficoll (Sigma). Contaminating erythrocytes were lysed by using a solution of 0.15 M NH4Cl, 10 mM KHCO3 and 1 mM sodium/EDTA (pH 7.0). After isolation, the number of viable cells was determined by trypan blue exclusion and the cells were resuspended at 3x106 cells ml–1 in RPMI medium containing 1 % L-glutamine for use in the chemokine-production assay.
Chemokine-production assays.
PBMCs isolated from mothers' blood samples and CBMCs, resuspended at 3x106 cells ml–1 in RPMI medium containing 1 % L-glutamine, were unstimulated or stimulated with phytohaemagglutinin (PHA) at a final concentration of 12.5 µg ml–1. Human serum (10 %) was then added to each well. Following 24 h incubation at 37 °C in a moist, 5 % CO2 atmosphere, culture supernatants were harvested and stored at –70 °C. Supernatants were tested for CCL3, CCL4 and CCL5 production by using Quantikine ELISA kits (R&D Systems).
Quantification of CCL3, CCL4 and CCL5 in plasma.
Peripheral levels of CCL3, CCL4 and CCL5 in the HIV-1-infected and -uninfected women in this study, and in the cord blood of infants born to these women, were quantified by using Quantikine ELISA kits (R&D Systems) according to the manufacturer's instructions.
Quantification of soluble immune-activation markers in cord-blood plasma.
2-Microglobulin and sL-selectin levels were determined by using Quantikine ELISA assays (R&D Systems) as described by the manufacturer. Neopterin levels were quantified by using an Immunotech ELISA system (Beckman Coulter). The minimum detectable dose of 2-microglobulin is <0.2 µg ml–1, for sL-selectin <0.3 ng ml–1 and for neopterin 0.2 ng ml–1.
HIV-1 quantification.
HIV-1 RNA levels (expressed as log10 units) were quantified by using the Roche Amplicor RNA Monitor assay (Roche Diagnostic Systems, Inc.) with a lower detection limit of 400 HIV-1 RNA copies ml–1.
DNA sequencing of CCL3 and CCL3-L1.
Genomic DNA was extracted from PBMCs by using a Qiagen QIAamp DNA minikit. One hundred nanograms of genomic DNA was used in a PCR amplification designed to co-amplify the region spanning the core promoter, exon 1 and most of intron 1 of both the CCL3 and CCL3-L1 genes. The upstream primer (5'-CTCCACAGCATCAGCCCAT-3') was designed to bind to a consensus region flanking the Alu element, which is present only in CCL3-L1, and the downstream primer (5'-CCGAGTCACAGCTCAGAAGA-3') was designed to bind to a consensus region in intron 1 that is approximately 50 bp upstream from the start of exon 2. The primers thereby amplified two fragments, a 1550 bp CCL3-L1-specific amplicon and a 1240 bp CCL3-specific amplicon. PCR was carried out by using the Expand High Fidelity system (Roche). Amplicons were subsequently purified by using a Qiagen QIAquick PCR Purification kit and sequenced by using four sequence-specific primers (5'-CACACTCACAGGAGAAACCATT-3', 5'-CTTCTGATCCCCGAGCA-3', 5'-GTGAGCGACCATGCCTG-3' and 5'-GCTTCTGATCCCTGAGTG-3'), designed to selectively sequence either the forward or reverse sequence of CCL3 and CCL3-L1 from the purified amplicon mixture. Sequencing reactions were set up by using Big Dye Terminator chemistry version 3.1 (Applied Biosystems) and run on a 3100 Genetic Analyser (Applied Biosystems). Resulting sequences were assembled and analysed for the presence of single-nucleotide polymorphisms (SNPs) by using the SEQUENCHER software version 4.1.4 (Gene Codes Corporation), by alignment with published sequences (Nakao et al., 1990) [GenBank accession nos D90144
[GenBank]
(CCL3) and D90145
[GenBank]
(CCL3-L1)].
Real-time PCR for CCL3-L1 copy-number determination.
The following primers and probes were synthesized (UCT): -globin gene upstream, 5'-GGCAACCCTAAGGTGAAGGC-3'; -globin gene downstream, 5'-GGTGAGCCAGGCCATCACTA-3'; -globin gene probe, 5'-CATGGCAAGAAAGTGCTCGGTGCCT-3'; CCL3-L1 gene upstream, 5'-TCTCCACAGCTTCCTAACCAAGA-3'; CCL3 and CCL3-L1 genes downstream, 5'-CTGGACCCACTCCTCACTGG-3'; CCL3-L1 gene probe, 5'-AGGCCGGCAGGTCTGTGCTGA-3' (Townson et al., 2002). In addition, CCL3 gene upstream 5'-TCTCCACAGCTTCCTAACCAAGC-3' and CCL3 gene probe 5'-AAGCCGGCAGGTCTGTGCTGA-3' were designed and synthesized. All probes were labelled with 5' 6-carboxyfluorescein (FAM) and a 3' 6-carboxytetramethylrhodamine (TAMRA) quencher.
Real-time PCR was performed by using an ABI Prism 7500 (Applied Biosystems) according to the protocol supplied. For each sample, the -globin, CCL3 and CCL3-L1 genes were amplified in duplicate, using approximately 20 ng genomic DNA per sample. CCL3 gene copy number was confirmed at two copies per diploid genome (p.d.g.) for each sample, calculated by using the relative-quantification method (as per the protocol supplied) and using -globin (present at two copies p.d.g.) as the endogenous control. CCL3 was then used as the endogenous control to calculate CCL3-L1 copy number, again using the relative-quantification method against a known-copy control. Samples giving a result of a single CCL3-L1 gene copy p.d.g. were confirmed by sequencing to ensure homozygosity.
Statistical analysis.
Levels of the chemokines and CCL3-L1 copy numbers were compared pairwise across the groups by using the non-parametric Mann–Whitney U test. Correlations were calculated by using the Spearman's Rank correlation coefficient. Multivariate analysis was conducted by using logistic-regression models. The statistical analyses were performed by using SPSS software (version 11.0; SPSS Inc.). All statistical tests were two-tailed and significance was considered to be P<0.05.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
). HIV-1-infected mothers were only identified as HIV-positive after birth; all children were given post-exposure prophylaxis with either nevirapine or zidovudine (Gray et al., 2005).
PHA-induced release of CCL3 from CBMCs was elevated significantly in the EU infants compared with the negative-control group (P=0.002) (Fig. 1b), suggesting that HIV-1 exposure in utero had primed elevated CCL3 production. Not surprisingly, IU-infected infants had the highest levels of spontaneous and PHA-induced production, consistent with the effects of an established infection (Fig. 1a, b). Most striking, however, was the finding that CBMCs from the IP infants produced significantly less PHA-induced CCL3 than CBMCs from the EU infants (P=0.001) and equivalent to that among the negative-control group (Fig. 1b), indicating that an infant deficiency of CCL3 production in the context of in utero viral exposure was associated with susceptibility to HIV-1 infection.
|
), although levels were generally lower and the differences between the groups were not as marked. In contrast, CCL5 production (Fig. 1g, h) was very low and spontaneous production was inhibited in infants born to HIV-positive mothers. There was no suggestion that a deficiency in production of CCL5 was associated with acquisition of infection.
Immune-activation events prior to birth do not account for differences in CCL3 production amongst EU and IP infants
We next tested whether the lower production of CCL3 in the IP infants might be the result of inadequate priming prior to birth. Levels of the soluble immune-activation markers neopterin (indicative of activation of monocytes and macrophages), 2-microglobulin (antigen-presenting cell and T-cell activation) and sL-selectin (shed from activated lymphocytes, monocytes and polymorphonuclear cells) were raised in plasma of infants born to HIV-1-infected mothers relative to negative controls (Fig. 2). However, there were no notable differences between EU and IP infants; thus, immune-activation events prior to birth did not account for their different CCL3 production.
|
). PHA-stimulated production of CCL3, as in the IP infants, tended to be lower among mothers transmitting intrapartum, but this did not reach statistical significance.
|
) and in cord-blood plasma of their infants (Fig. 1c, f, i). CCL3 levels in HIV-1-infected mothers who transmitted intrapartum were significantly lower (P=0.036) than levels among infected mothers who did not transmit (EU). IU mothers tended to have elevated peripheral levels of CCL3 (Fig. 3c), reflecting the unstimulated production by PBMCs observed in Fig. 3(a). Cord-blood plasma levels did not distinguish between EU and IP.
Relationship between CCL3 and transmission is not explained by mothers' viral load or CD4 T-cell count
No associations were found between the ability of infant CBMCs to produce CCL3 and maternal HIV-1 viral load or CD4 T-cell count. Adjusting statistically for maternal viral load and CD4 count, the association between decreased levels of CBMC PHA-stimulated CCL3 and increased risk of intrapartum infection remained significant (P=0.039).
Reduced CCL3-L1 copy number in infants is associated with maternal–infant HIV-1 transmission
On the basis of our mother–child CCL3 production data, we questioned which host genotypes might be responsible for the differences in induced production. In humans, CCL3 is encoded by two functional genes (CCL3/LD78
and CCL3-L1/LD78) and a pseudogene, LD78
(Menten et al., 2002). CCL3 occurs as two copies p.d.g., whereas CCL3-L1 occurs in variable copy number in different individuals. Increased CCL3-L1 gene copy number has been correlated with increased CCL3 production in lipopolysaccharide-stimulated monocytes (Townson et al., 2002), making copy number of this particular gene a likely candidate for differential CCL3 production in vivo. In a recent study, Argentinian children with CCL3-L1 copy numbers lower than their population median had a higher risk of acquiring HIV-1 vertically (Gonzalez et al., 2005).
For copy-number determinations of CCL3 and CCL3-L1, we included additional mother–child pairs from the same hospital (Kuhn et al., 2001b) to make up a larger cohort of 74 non-transmitting and 46 transmitting mother–child pairs. The CCL3 gene was consistently found to be present at two copies p.d.g. in all samples tested. Despite a trend towards reduced copy numbers of CCL3-L1 amongst transmitting mothers (median 4, range 3–8) when compared with non-transmitting mothers (median 5, range 2–8), this was not statistically significant. However, when comparing CCL3-L1 copy numbers amongst infants born to HIV-1-infected mothers (Fig. 4), these were reduced significantly among those who became infected (median 4, range 1–10) relative to those who remained uninfected (median 5, range 1–8) (P=0.019), confirming that the risk of acquiring HIV-1 is the result of susceptibility of the infant rather than simply due to a transmissibility factor of the mother. There was no relationship between maternal viral load or CD4 counts and their infants' copy number of CCL3-L1.
|
). This was most marked if CCL3-L1 copy number was high (at least four copies), suggesting the existence of non-functional copies in IP infants.
|
) were sequenced for the mothers who had CCL3 production levels determined (Fig. 3a–c) and their matched infants [i.e. a total of 86 sequences each for CCL3 (1240 bp) and CCL3-L1 (1550 bp)]. These regions were selected based on former descriptions of associations with HIV/AIDS (Gonzalez et al., 2001) and on likelihood of effects on gene transcription. Data revealed the presence of four SNPs in CCL3 and three in CCL3-L1.
|
), it was evident that the SNPs described previously as occurring together in intron 1 at positions p+199 and p+545 (p+113 and p+459 on the chimpanzee CCL3 gene, respectively) (Gonzalez et al., 2001) were, in all instances, associated with a newly identified SNP (C
T) in the promoter region at p–86. This particular three-SNP haplotype was encountered more frequently in the IP infants (5/13) and their mothers (5/13) than amongst EU infants (3/13) or their HIV-1-infected mothers (2/13), but, given the small numbers, was not statistically significant. The SNP at p+702 (GC) occurred rarely, independently of the three-SNP haplotype.
No variations in nucleotide sequence were noted in the promoter region of CCL3-L1 (Fig. 6b).The only noteworthy changes between groups in the CCL3-L1 gene were at p+480, where four of 13 IP infant samples were homozygous for C, whereas for EU infants, three of 13 were homozygous for G (ancestral), therefore earmarking this site as a potential candidate for altered CCL3 production.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
We propose the following model for the role of CCL3 in protective immunity to HIV-1. Given that most vertical transmission occurs with R5 isolates (LaRussa et al., 2002; Ometto et al., 1995), it is not unexpected that the CC chemokines, being natural ligands for the HIV-1 co-receptor CCR5, may influence this mode of transmission through non-cytolytic inhibition of infection. The fact that copy number of CCL3-L1 in particular associates with risk of transmission, as does induced production of CCL3, suggests a ‘more expression, more protein’ quantitative effect, identifying CCL3-L1 as playing a more prominent role in protection than CCL3, which did not vary from two copies p.d.g. in all individuals tested. In this regard, proteins produced from the CCL3 and CCL3-L1 genes have been shown to have distinct biological functions, with CCL3-L1 being 30-fold more potent at inhibiting HIV-1 infection (Aquaro et al., 2001; Menten et al., 1999; Nibbs et al., 1999, 2001). Post-translational modification by amino-terminal truncation of CCL3-L1 by CD26/DPP (dipeptidyl peptidase), present in plasma and highly expressed on a number of cell types (Van Damme et al., 1999), gives rise to a –2 variant form that is even more potent an agonist and HIV-1 inhibitor (Proost et al., 2000; Struyf et al., 2001). It stands to reason that increased copies of CCL3-L1 that encode protein with greater anti-HIV activity would present a distinct advantage at first encounter with HIV-1, purely on the basis of the ability of CCL3 to block HIV-1 entry into target cells through steric hindrance or downregulation of the CCR5 receptor. However, our data would also suggest that this mechanism is unlikely to be the only one at play and, in particular, that CCL4 and CCL5 cannot compensate for lack of CCL3, further supporting the hypothesis that immune functions unique to CCL3 are involved in protection from HIV-1.
A successful antiviral response, facilitated by CCL3, could be envisaged to occur in two phases, the first involving acute inflammatory effects of CCL3, which establish the recruitment of specific cell types in response to HIV-1 challenge, a concentration-dependent process. A deficit in CCL3 production at this point may alter all subsequent events substantially. The second phase would involve the effects of CCL3 on adaptive immunity. Studies in mice immunized with protein have shown that, if given in addition, chemokines such as lymphotactin (Lillard et al., 1999), CCL5 (Lillard et al., 2001) and, more recently, CCL3 and CCL4 (Lillard et al., 2003) could potentiate both humoral and cell-mediated adaptive mucosal and systemic immunity. The distinct differences in activities of CCL3 and CCL4 (Lillard et al., 2003) can help to explain why increased levels of CCL4 primed by exposure to HIV-1 in utero did not compensate for lack of CCL3 production in those infants who became infected. In particular, CCL3, but not CCL4, promotes both mucosal and systemic cytotoxic T-lymphocyte responses. CCL3 also promotes strong antigen-specific serum IgG and IgM responses, enhances T-helper type 1 responses and modulates costimulatory molecules on T cells and antigen-presenting cells (Lillard et al., 2003). Interestingly, we have observed previously (Kuhn et al., 2001a, b) that Env-specific, interleukin 2-dependent cellular immune responses were only detected in cord blood of exposed–uninfected infants and not in infants who subsequently become infected, consistent with the notion that deficient CCL3 production may compromise the development of primary immune responses to HIV-1. In further support of this, Wasik et al. (1999) also observed that HIV-1 Env-specific T-helper cell responses detected in exposed–uninfected infants were associated with the enhanced expression of CC chemokines. The fact that we do not observe a threshold of CCL3 production that is fully protective against transmission suggests that CCL3 alone is insufficient and may be an important part of the multifactorial immune responses necessary to protect against HIV-1 at varying extents of viral exposure.
In contrast to the mothers transmitting intrapartum, mothers transmitting intrauterine had elevated peripheral levels of CCL3. These levels correlated with higher levels of spontaneous release from PBMCs of CCL3, suggesting that increased peripheral production was probably the result of activated cells in the peripheral circulation. As sample numbers are small, it will be important to verify this further, as it suggests that consequences of CCL3 may be different for in utero infection. Whether this is merely a marker of the very much elevated immune activation that is characteristic of these mothers or that CCL3 itself impacts negatively on transmission due to high levels of CCL3 at the maternal–fetal interface remains to be established. CCL3 produced by placental cytotrophoblasts has been shown to attract monocytes, natural killer and T cells to sites adjacent to the trophoblast (Drake et al., 2001) and the extent of production may determine cell infiltration and likelihood of protection from, or infection with, HIV-1.
Our findings are consistent with the novel findings on gene copy number (Gonzalez et al., 2005) in raising the importance of CCL3 in HIV susceptibility. We also show that ‘not all CCL3-L1 gene copies are created equal’ and it will be important to identify the precise genetic determinants that define levels of CCL3 production, so that genotypic assays can be developed that identify individuals at increased risk of infection or hastened disease progression. Mutations within some of the duplicated copies may render them less or non-functional; this may explain why absolute copy number per se does not associate with protection, but the copy number in relation to the specific population median does (Gonzalez et al., 2005).
Given the challenges in developing successful vaccines to HIV-1 (Brander & Walker, 2003; Stratov et al., 2004), it would be advantageous if non-specific immune parameters, able to provide protection and/or augment HIV-specific responses, were identified. For example, a recent macaque study demonstrated proof of principle that an artificially created CCL5 could be an effective microbicide for prevention of vaginal simian–human immunodeficiency virus infection (Lederman et al., 2004). CCL3 would represent an excellent adjuvant for inclusion in an HIV vaccine construct, but the question remains as to how to compensate for the loss of function in vaccinees that have a deficient CCL3-production phenotype. Host genetics need to be taken into consideration in vaccine evaluation, and vaccines should ideally elicit immune responses that produce sufficient CCL3 at the site of subsequent antigen–HIV-1 encounter. This underscores the need to find natural or other molecules that, under certain conditions of stimulation, may compensate for lack of CCL3 function. Therefore, it is imperative to delineate the precise roles in the immune response of CCL3, aside from its non-cytolytic inhibitory effect on HIV-1, as its role in driving the development of adaptive immunity may be crucial to protection.
|
ACKNOWLEDGEMENTS |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
isoform of MIP-1 is the most potent CC-chemokine in inhibiting CCR5-dependent human immunodeficiency virus type 1 replication in human macrophages. J Virol 75, 4402–4406.Brander, C. & Walker, B. D. (2003). Gradual adaptation of HIV to human host populations: good or bad news? Nat Med 9, 1359–1362.[CrossRef][Medline]
Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C. & Lusso, P. (1995). Identification of RANTES, MIP-1, and MIP-1 as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815.
Deng, H., Liu, R., Ellmeier, W. & 12 other authors (1996). Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666.[CrossRef][Medline]
Dragic, T., Litwin, V., Allaway, G. P. & 8 other authors (1996). HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673.[CrossRef][Medline]
Drake, P. M., Gunn, M. D., Charo, I. F., Tsou, C.-L., Zhou, Y., Huang, L. & Fisher, S. J. (2001). Human placental cytotrophoblasts attract monocytes and CD56bright natural killer cells via the actions of monocyte inflammatory protein 1. J Exp Med 193, 1199–1212.
Goila, R., Kumar, F. & Banerjea, A. C. (2001). MIP-1 promoter polymorphism in humans and monkeys: identification of two polymorphic regions characterized by the insertion of unique sequences in monkeys. AIDS 15, 1065–1067.[CrossRef][Medline]
Gonzalez, E., Dhanda, R., Bamshad, M. & 13 other authors (2001). Global survey of genetic variation in CCR5, RANTES, and MIP-1: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci U S A 98, 5199–5204.
Gonzalez, E., Kulkarni, H., Bolivar, H. & 19 other authors (2005). The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440.
Gray, G. E., Urban, M., Chersich, M. F., Bolton, C., van Niekerk, R., Violari, A., Stevens, W. & McIntyre, J. A. (2005). A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS 19, 1289–1297.[Medline]
Heeney, J. L., Teeuwsen, V. J. P., van Gils, M. & 9 other authors (1998). -Chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques. Proc Natl Acad Sci U S A 95, 10803–10808.
Kuhn, L., Coutsoudis, A., Moodley, D., Trabattoni, D., Mngqundaniso, N., Shearer, G. M., Clerici, M., Coovadia, H. M. & Stein, Z. (2001a). T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breast-feeding transmission. AIDS 15, 1–9.[CrossRef][Medline]
Kuhn, L., Meddows-Taylor, S., Gray, G., Trabattoni, D., Clerici, M., Shearer, G. M. & Tiemessen, C. (2001b). Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal–infant transmission. Clin Exp Immunol 123, 443–450.[CrossRef][Medline]
LaRussa, P., Magder, L. S., Pitt, J. & 8 other authors (2002). Association of HIV-1 viral phenotype in the MT-2 assay with perinatal HIV transmission. J Acquir Immune Defic Syndr 30, 88–94.[CrossRef][Medline]
Lederman, M. M., Veazey, R. S., Offord, R. & 9 other authors (2004). Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306, 485–487.
Lehner, T., Wang, Y., Cranage, M. & 11 other authors (1996). Protective mucosal immunity elicited by targeted iliac lymph node immunization with a subunit SIV envelope and core vaccine in macaques. Nat Med 2, 767–775.[CrossRef][Medline]
Lillard, J. W., Jr, Boyaka, P. N., Hedrick, J. A., Zlotnik, A. & McGhee, J. R. (1999). Lymphotactin acts as an innate mucosal adjuvant. J Immunol 162, 1959–1965.
Lillard, J. W., Jr, Boyaka, P. N., Taub, D. D. & McGhee, J. R. (2001). RANTES potentiates antigen-specific mucosal immune responses. J Immunol 166, 162–169.
Lillard, J. W., Jr, Singh, U. P., Boyaka, P. N., Singh, S., Taub, D. D. & McGhee, J. R. (2003). MIP-1 and MIP-1 differentially mediate mucosal and systemic adaptive immunity. Blood 101, 807–814.
Matsukawa, A., Hogaboam, C. M., Lukacs, N. W. & Kunkel, S. L. (2000). Chemokines and innate immunity. Rev Immunogenet 2, 339–358.[Medline]
Menten, P., Struyf, S., Schutyser, E., Wuyts, A., De Clercq, E., Schols, D., Proost, P. & Van Damme, J. (1999). The LD78 isoform of MIP-1 is the most potent CCR5 agonist and HIV-1-inhibiting chemokine. J Clin Invest 104, R1–R5.
Menten, P., Wuyts, A. & Van Damme, J. (2002). Macrophage inflammatory protein-1. Cytokine Growth Factor Rev 13, 455–481.[CrossRef][Medline]
Nakao, M., Nomiyama, H. & Shimada, K. (1990). Structures of human genes coding for cytokine LD78 and their expression. Mol Cell Biol 10, 3646–3658.
Nibbs, R. J. B., Yang, J., Landau, N. R., Mao, J.-H. & Graham, G. J. (1999). LD78 a non-allelic variant of human MIP-1 (LD78), has enhanced receptor interactions and potent HIV suppressive activity. J Biol Chem 274, 17478–17483.
Nibbs, R. J. B., Kriehuber, E., Ponath, P. D. & 8 other authors (2001). The -chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. Am J Pathol 158, 867–877.
O'Brien, S. J. & Nelson, G. W. (2004). Human genes that limit AIDS. Nat Genet 36, 565–574.[CrossRef][Medline]
Ometto, L., Zanotto, C., Maccabruni, A., Caselli, D., Truscia, D., Giaquinto, C., Ruga, E., Chieco-Bianchi, L. & De Rossi, A. (1995). Viral phenotype and host-cell susceptibility to HIV-1 infection as risk factors for mother-to-child HIV-1 transmission. AIDS 9, 427–434.[Medline]
Paxton, W. A., Martin, S. R., Tse, D. & 8 other authors (1996). Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat Med 2, 412–417.[CrossRef][Medline]
Proost, P., Menten, P., Struyf, S., Schutyser, E., De Meester, I. & Van Damme, J. (2000). Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78 into a most efficient monocyte attractant and CCR1 agonist. Blood 96, 1674–1680.
Stratov, I., DeRose, R., Purcell, D. F. J. & Kent, S. J. (2004). Vaccines and vaccine strategies against HIV. Curr Drug Targets 5, 71–88.[CrossRef][Medline]
Struyf, S., Menten, P., Lenaerts, J.-P., Put, W., D'Haese, A., De Clercq, E., Schols, D., Proost, P. & Van Damme, J. (2001). Diverging binding capacities of natural LD78 isoforms of macrophage inflammatory protein-1 to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils. Eur J Immunol 31, 2170–2178.[CrossRef][Medline]
Townson, J. R., Barcellos, L. F. & Nibbs, R. J. B. (2002). Gene copy number regulates the production of the human chemokine CCL3-L1. Eur J Immunol 32, 3016–3026.[CrossRef][Medline]
Van Damme, J., Struyf, S., Wuyts, A., Van Coillie, E., Menten, P., Schols, D., Sozzani, S., De Meester, I. & Proost, P. (1999). The role of CD26/DPP IV in chemokine processing. Chem Immunol 72, 42–56.[Medline]
Wasik, T. J., Bratosiewicz, J., Wierzbicki, A. & 9 other authors (1999). Protective role of -chemokines associated with HIV-specific Th responses against perinatal HIV transmission. J Immunol 162, 4355–4364.
Zagury, D., Lachgar, A., Chams, V. & 11 other authors (1998). C-C chemokines, pivotal in protection against HIV type 1 infection. Proc Natl Acad Sci U S A 95, 3857–3861.
Received 24 November 2005;
accepted 5 March 2006.
This article has been cited by other articles:
|
|
 |
|
  D. B. Schramm, S. Meddows-Taylor, G. E. Gray, L. Kuhn, and C. T. Tiemessen Low Maternal Viral Loads and Reduced Granulocyte-Macrophage Colony-Stimulating Factor Levels Characterize Exposed, Uninfected Infants Who Develop Protective Human Immunodeficiency Virus Type 1-Specific Responses Clin. Vaccine Immunol., April 1, 2007; 14(4): 348 - 354. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| INT J SYST EVOL MICROBIOL | MICROBIOLOGY | J GEN VIROL |
| J MED MICROBIOL | ALL SGM JOURNALS | |
