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Although a major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is to elicit broad and potent neutralizing antibodies (NAbs), there are no data that directly demonstrate a role for such NAbs in protection from HIV-1 infection in exposed humans. The setting of mother-to-child transmission provides an opportunity to examine whether NAbs provide protection from HIV-1 infection because infants acquire passive antibodies from their mothers prior to exposure to HIV-1 through breastfeeding. We evaluated the characteristics of HIV-1-specific NAbs in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and monitored them until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. From their mothers, infants acquired broad and potent NAbs that were capable of recognizing heterologous circulating HIV-1 variants of diverse subtypes, but the presence of NAbs of broad HIV-1 specificity was not associated with transmission risk. There was also no correlation between responses to any particular virus tested, which included a range of diverse variants that demonstrated different neutralization profiles, including recognition by specific antibodies with known epitope targets. The eight viruses tested exhibited neutralization profiles to a variety of monoclonal antibodies (2F5, PG9, and VRC01) similar to those of viruses present in pregnant women in the cohort. These results suggest that the breadth and potency of the heterologous antibody response in exposed infants, measured against a virus panel comprised of variants typical of those circulating in the population, does not predict protection.
At present, there is considerable effort being directed toward identifying human immunodeficiency virus type 1 (HIV-1) vaccine immunogens that elicit broadly neutralizing antibody (NAb) responses (13). This approach is predicated, in part, on the fact that the effective protection afforded by most vaccines is due to antibody responses (21). Moreover, the results of passive immunization studies in the macaque model have demonstrated that antibodies capable of neutralizing an incoming HIV-1 (simian-human immunodeficiency virus [SHIV]) strain can block infection, including through intravenous, vaginal, and oral routes (1, 8, 12, 18, 19, 27–29, 34, 37, 48). Despite the fact that the antibody levels used to achieve protection were very high in these initial studies, the results provided proof of principle that HIV-1-specific antibodies can block HIV-1 infection. In a more recent study, lower antibody levels, closer to those found in natural HIV-1 infection, were shown to delay infection in a low-dose SHIV/macaque challenge model (18). However, in these experiments, the virus used for challenge was one that was exquisitely sensitive to neutralization by the passive antibody tested compared to other strains of HIV-1 (47, 50).
For NAbs to be effective in stopping HIV-1 transmission in humans, it is critical that they have broad specificity and be capable of blocking diverse circulating HIV-1 strains, which can differ by more than 30% in their envelope sequences and by more than 5,000-fold in their neutralization sensitivities (4, 47, 50). Indeed, there are no data that clearly show whether preexisting HIV-specific NAbs in an exposed human will provide protection from infection. In addition, because the animal model studies are limited to analysis of a very few select challenge strains, little is known regarding the antibody specificity that would confer the greatest protection against HIV-1 transmission in humans. Thus, studies that directly test whether NAbs, when present at physiological levels, can reduce the risk of HIV-1 acquisition are critical in helping shape the way forward for HIV-1 vaccine design.
Mother-to-child transmission (MTCT), including transmission by breastfeeding, offers a unique opportunity to explore this question because maternal antibodies are shared with the infant starting in pregnancy and are therefore a potential source of some protection against HIV-1 infection in that setting. Recent studies indicate that the viruses in breast milk and blood are intermingled and are not generally compartmentalized (15, 17), suggesting that breast milk viruses are typical of circulating viruses. Moreover, the probability of infection per exposure during breastfeeding, measured either as per liter of breast milk ingested or by daily exposure, is generally similar to the probability of infection from one unprotected exposure during sexual transmission (38).
To date, MTCT studies have focused on the protective role of antibodies in the infected mother, which does not directly address the situation envisioned in current vaccine approaches—namely, that the antibodies will exert their effects in the exposed, uninfected individual. Nonetheless, studies of maternal antibodies provide some suggestion of a protective role for NAbs. Several early studies, each relatively small, showed that nontransmitting mothers had more frequently detected and/or higher levels of NAb responses than transmitting mothers, suggesting a role for NAb in reducing MTCT (7, 16, 22, 45, 46). A correlation between maternal antibodies and transmission risk was also observed in a larger study of Thai women (n = 90), in which the potency of NAb responses to 2 of 4 viruses tested inversely correlated with transmission (2, 43). Subsequent studies showed that the variants transmitted to infants tended to be those in the mother that were the most resistant to NAbs (10, 51). Together, these studies suggest that the nature and specificity of the NAb response in the mother may influence the risk of HIV-1 acquisition by the infant. However, to date, no one has examined the characteristics of the passively acquired HIV antibodies in the infant and whether they play any role in protecting infants from HIV-1 infection, particularly during the intrapartum and breastfeeding periods, which are times when these antibody levels are expected to be high. Because the infant may have passively acquired HIV-specific antibodies at the time of HIV-1 exposure, infants with broad and potent NAb responses would be expected to be less susceptible to infection if such responses are protective.
At present, the breadth of NAb responses is typically defined against a panel of genetically diverse recently transmitted HIV-1 variants to best assess their potential to neutralize circulating strains (4, 5, 24, 25). NAb breadth, as defined in this manner, is used to identify individuals with potentially desirable NAb responses to mimic in vaccine design, such as responses to conserved epitopes, and is likely to be used to determine which vaccine immunogens have potential for efficacy. Here, we examined whether the breadth of antibody responses, as defined by the ability to neutralize a diverse virus panel, correlates with protection from infection in the setting of MTCT.
Samples were from a randomized clinical trial in Nairobi, Kenya, conducted from 1992 to 1998 to compare HIV-1 transmission in breastfeeding infants to that in formula-feeding infants. Enrollment, counseling, and the specific methods of the study have been described elsewhere (31). Infant infection status, maternal plasma viral load and breast milk viral load, maternal CD4 and CD8 T cell counts, and infant viral loads were available, and the relevant laboratory methods are described elsewhere (20, 32, 42). None of the women or infants in the study received antiretroviral therapy. The ethical review committees of the University of Nairobi, the University of Washington, and the Fred Hutchinson Cancer Center approved the study.
The mother was randomized to breastfeeding in the clinical trial (31), the infant was HIV-1 DNA PCR negative at the time of birth, an infant serum sample was available from either cord or peripheral blood from the first week of life, and subsequent HIV-1 DNA test results were available to determine infection status and to estimate the time of infection. One hundred mother-infant pairs who met these criteria were identified.
Pseudovirus particles were generated in 293T cells by cotransfecting the full-length envelope clone with a subtype A proviral clone lacking an envelope (Q23Denv) as described previously (5, 51). Virus was harvested at 48 h posttransfection, the supernatant was filtered through a 0.22-micron-pore-size filter, and the infectious titer was determined by infecting TZM-bl cells (obtained through the NIH AIDS Research and Reference Reagent Program; kindly supplied by John Kappes) and visually counting infected cells.
Eight envelope variants representing recently transmitted HIV-1s from different subtypes were used to generate the virus panel (Table 1). The panel was weighted toward viruses from the study region, as they best represent variants circulating in the cohort under study (n = 6), but it also included two viruses from other geographic areas to optimally probe for broad NAb responses. The eight viruses spanned a range of neutralization sensitivities, including tier 1B and tier 2 viruses (Table 1). The virus panel included four clones from Kenyan women infected through sexual contact (Q461d1, Q168b23, Q842d16, and QD435.100ENV.A4; subtypes A and D [4, 5, 26]), two from Kenyan infants infected during the postpartum period (BJ613.E1 and BF535.A1; subtypes A and A/D [51]), one from a U.S. man infected by another man (THRO4146.18/SVPB15; subtype B [24]), and one from a South African woman infected through heterosexual contact (DU156.12/SVPC3m; subtype C [25]) (Table 1).
Envelope variants representing maternal viruses were described previously (51). To represent the spectrum of neutralization sensitivities of maternal variants, we chose two variants, the one that was most sensitive and the one that was most resistant to autologous maternal antibodies based on previous studies (51).
The TZM-bl neutralization assay has been described in detail elsewhere (5, 51). Briefly, 500 50% tissue culture infective doses (TCID50) were mixed with infant plasmas in triplicate at 37°C. Six 2-fold plasma dilutions were tested, starting at 1:50 for Q461d1 and Q168b23, the two variants known to be the most neutralization sensitive, and 1:25 for all other variants (4, 5, 26). In the case of monoclonal antibodies (MAbs), six 2-fold dilutions were also tested, starting at an initial concentration that ranged from 1 μg/ml to 25 μg/ml, depending on the sensitivity of the virus being tested to a given MAb. After 60 min, 10,000 TZM-bl cells in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and l-glutamine were added to each well. β-Galactosidase levels were measured using the Galacto-Light system (Applied Biosystems, Foster City, CA) at 48 h postinfection (51). The concentration of plasma that resulted in 50% inhibition of virus infection (IC50) was determined as described previously (51).
Data from all eight pseudoviruses were used to define a breadth and potency neutralization score for each infant plasma sample, as described previously (9, 11, 36, 37, 40, 44). This scoring system accounts for the differences in neutralization sensitivity of the different viruses tested. To define breadth, each plasma-virus combination was scored as 0 or 1 by comparing the IC50 value for that plasma sample to those of all other plasma samples tested with the same virus. A 1 was given when the IC50 was above the median for all plasma samples for that virus and a zero when it was below the median. Potency was defined by taking the IC50 value for a given plasma-virus combination and dividing it by the median IC50 value for that virus across all plasma samples.
NAb data used for analyses included the median IC50 values for each infant plasma-virus combination determined independently as well as the calculated breadth and potency. For plasma that did not neutralize at the highest concentrations, the midpoint value between the lowest dilution and 0 was used for analysis. Continuous data were compared using the Mann-Whitney U test. Maternal viral load, NAb breadth and potency, and individual IC50 responses were tested for correlation using the Spearman rank method. The time to the first HIV-1 DNA PCR positive test from birth to 24 months was used for Kaplan-Meier and Cox regression analyses.
An IC50 heat map was generated using R software (R Development Core Team, R Foundation for Statistical Computing, Vienna, Austria, 2008) and the heatmap.2 (Andy Liaw, original; R. Gentleman, M. Maechler, W. Huber, G. Warnes, revisions) and RColorBrewer version 1.0-2 (Erich Neuwirth) packages. All IC50 values were log transformed prior to analysis.
Mother-infant pairs from the Nairobi Breastfeeding Trial were included in the study if they met the following criteria: the mothers were randomized to breastfeeding in the original study (31), the infant was HIV-1 DNA PCR negative at the time of birth, and an infant serum sample was available from either cord or peripheral blood from the first week of life. One hundred mother-infant pairs meeting these criteria were included in the present study. The mean duration of breastfeeding among these women was 21.3 months, ranging from <1 month to ≥24 months (the end of the follow-up period). Of the 100 infants, 32 (32%) infants who were HIV-1 DNA negative at birth became positive before the end of the follow-up period at 2 years (Fig. 1). The median maternal CD4 T-cell count was 410 cells/μl (n = 93; range, 10 to 1,165 cells/μl), and the median maternal plasma viral load was 4.67 log10 HIV-1 RNA copies/ml (n = 96; range, 1.77 to 6.93 log10 HIV-1 RNA copies/ml) at or near 32 weeks gestation (Table 2). Most women (59%) had CD4 T-cell counts between 200 and 500, 33% had CD4 T-cell counts of >500, and only 8% had CD4 T-cell counts of <200. The median breast milk viral load obtained from samples during the first postnatal week was 2.59 log10 HIV-1 RNA copies/ml (n = 55; range, 1.18 to 5.29 HIV-1 RNA copies/ml). Of 89 women for whom HIV-1 subtype information was available (32), 59 were infected with subtype A, 21 with subtype D, 8 with subtype C, and 1 with an A/D intersubtype recombinant.
Mothers that transmitted HIV-1 to their infants had lower CD4 counts (329 cells/ml) and higher viral loads (5.0 log10 HIV-1 RNA copies/ml) than nontransmitting mothers (CD4 count, 451 cells/μl, P = 0.02; viral load, 4.51 HIV-1 log10 copies/ml, P = <0.001) (Table 2). The median viral load in the infected infants was 6.25 log10 HIV-1 RNA copies/ml (n = 29; range, 4.09 to 7.54 log10 HIV-1 RNA copies/ml).
Of the 100 infant plasma samples examined for the presence of HIV-specific NAbs, 99 had antibodies capable of neutralizing at least one of the eight HIV-1 variants tested (Fig. 2). This panel included variants isolated soon after infection for both infants and adults and included subtype A, B, C, and D variants (Table 1). Importantly, this panel, which included primarily tier 2 variants, also included variants sensitive to MAbs that recognize the CD4 binding site (b12) and the membrane proximal region of the transmembrane domain (2F5 and 4E10). Forty-nine of the infant plasma samples had detectable NAb activity against all eight viruses, and 74 neutralized more than half of the variants tested.
The mean IC50 values for the eight viruses tested spanned a median of 863 for a highly sensitive subtype A variant (Q168b23; range, ≤50 to 1,700) to 40 for the subtype B variant, B15 (range, ≤25 to 333) (Table 2). The IC50 values for the uninfected infants were in general very similar to those for 70 chronically infected Kenyan women in a prior study (36). Of the three viruses that were tested in common in both studies, the median IC50 values for infants who had passive antibodies from their mothers were within 3-fold of those for chronically infected women (Q168b23, 863 versus 312; Q461d1, 278 versus 441; Q842d16, 47 versus 140 for the infants and women, respectively).
Because prior studies demonstrated a positive correlation between plasma viral load and NAb levels within an individual (9, 11, 35, 36, 40, 44), we examined the relationship between passive antibody measures for infants and viral load in their mothers. Maternal viral load did not correlate with the IC50 values for any of the eight variants individually, although one variant, Q168b23, showed a statistical trend (P value range, 0.07 to 0.99). The breadth and potency of the NAb response across the virus panel were also examined, using a method that accounts for the variable neutralization sensitivity of the viruses tested, the same method used in a prior study that examined NAb breadth and its relation to viral load in chronically infected women (36). Maternal viral loads were not correlated with either the breadth (P = 0.6) or the overall potency (P = 0.7) of the neutralizing antibody response in the infants. Similarly, neither maternal CD4 count nor breast milk HIV-1 RNA viral load was correlated with the breadth or potency of HIV-specific NAbs in the infants (data not shown).
The relationship between infant passively acquired HIV-specific NAbs and the infant's risk of HIV-1 acquisition was examined. For each of the eight viral variants tested here, there was no significant difference in the distribution of the IC50 values between the HIV-positive and HIV-negative infants (Table 2). Composite scores representing the breadth of antibody neutralization or the potency of individual responses also did not differ between groups.
Another method used to examine the relationship between NAbs and infant infection was Kaplan Meier analysis incorporating either neutralization potency or breadth with time to HIV-1 as the outcome. In these models, there was no difference in time to infection between the quartile of infants with the highest neutralization potency scores and those with the lowest scores (Fig. 3a). Similar results were observed when the breadth scores (Fig. 3b) and the IC50 values for individual viruses (data not shown) were tested in this model. Results were similar with Cox proportional hazard models that adjusted for maternal viral load (data not shown).
The above analyses compared NAb levels within the first week of life with the subsequent transmission risk due to breastfeeding through 2 years of life. To address whether such antibodies persisted during the period of breast milk exposure, we examined NAb levels over time in infants who had the highest potency scores (>25) and had available samples at multiple times, including 0 and 6 weeks as well as 3 and 6 months after birth (n = 5) (Fig. 4). We also examined four infants with moderate potency scores but with antibodies capable of neutralizing the most sensitive viruses, Q168b23 and Q461.d1, which were used to examine NAb decay. In all cases, there was a decline in IC50 values over each time point tested. There was an ~20-fold reduction in titer against Q168b23 (range, 2- to 54-fold), but NAbs could be detected through 6 months of life in most cases. Only two of the infant plasma samples showed detectable neutralization against the Q461d1 pseudovirus 6 months after birth.
Because passively acquired NAbs decayed over the first 6 month of life, their potential role in blocking HIV-1 infection could be limited to this early breastfeeding period. Therefore, we performed the analyses described above, restricting infected infants to those who were HIV positive at 6 weeks or 6 months of life. For this purpose, we compared all measures of neutralization (the IC50 values for each variant as well as the breadth and potency scores) between infants infected in the first 6 weeks of life (n = 14) and all other infants (n = 86) (Table 3) as well as between infants infected during the first 6 months of life (n = 21) and all others (n = 79) (Mann-Whitney U test) (Table 4). In this analysis, there were no differences in the individual mean IC50 values, breadth scores, or potency scores between infants who became infected and those who were not infected in the defined interval for either of these comparisons (Tables 3 and and44).
To determine if the viruses in the panel were representative of those found in mothers in the cohort, we examined the neutralization sensitivities of maternal viruses generated from envelope variants cloned directly from blood taken at delivery from six transmitting mothers in the Nairobi Breastfeeding Trial (51). For this purpose, we used three MAbs with broad specificities targeted to distinct regions of the envelope protein: 2F5, which targets an epitope in the membrane proximal region of gp41 (30), VRC01, which targets the CD4 binding site (52), and PG9, which targets a quaternary epitope formed by conserved residues in V2 and V3 (50). The maternal variants had a range of neutralization sensitivities to these MAbs (Table 5). About half of the maternal viruses showed no detectable neutralization with 2F5 at the highest concentration tested, which was similar to what was observed for viruses from Kenya in general (4, 5), including the virus panel (Table 1). The majority of maternal viruses were neutralized by VRC01 and PG9, but there was a range of IC50 values, from 0.03 to >10 μg/ml. An identical range of IC50 values with these MAbs, from 0.03 to 10 μg/ml, was observed across the 8-virus panel (Table 1). Some mothers had two variants that were both sensitive to a particular MAb (e.g., ML274 for PG9 and VRC01), others had a mixture of sensitive and resistant viruses (e.g., MK184 for PG9 and VRC01), while others had two viruses that were both resistant to a particular MAb (e.g., MJ613 and 2F5). There was no apparent relationship between sensitivity to any particular MAb and sensitivity to autologous plasma. For example, in some cases the virus was sensitive to plasma and resistant to PG9 (e.g., MF535.B1), in other cases the converse was true (e.g., MJ613.C7), and in still others, the virus was sensitive to both (e.g., MK184.G3) or resistant to both (e.g., MK184.E4).
Infants of HIV-1-positive mothers have passively acquired HIV-specific NAbs at the time of virus exposure, and thus represent a unique setting to examine the potential for such antibodies to impact the risk of HIV-1 acquisition. Here we found that infants who remained uninfected with HIV had NAb breadth and potency at birth similar to those who became HIV infected. Thus, despite the presence of these HIV-specific antibodies, there is no evidence that they provide any protection from infection in exposed infants. There was no correlation between the infant infection status at 6 weeks, 6 months, or 24 months of life and the breadth and potency of passively acquired HIV-specific NAbs in infants.
Virtually all infants (99%) had antibodies capable of neutralizing at least one of the viruses that were generated from a panel of eight envelope variants representing both vertically and sexually transmitted HIV-1s of diverse subtypes (4, 5, 51). Importantly, this virus panel included variants that were sensitive to CD4 binding site antibodies (VRC01 and b12), antibodies that recognized a quaternary epitope on the surface unit (PG9), and antibodies directed to the membrane proximal domain of the transmembrane protein (4E10 and 2F5). Thus, the selected viruses provided a surrogate measure of whether antibodies directed to the epitopes recognized by broadly neutralizing antibodies, which are presumably accessible on variants that are neutralized by the MAbs, may play a role in protection. However, there was no association between the infants' ability to neutralize any of these viruses individually and subsequent acquisition, even when controlling for maternal viral load.
In order to determine whether unique characteristics of the maternal viruses could make them less sensitive to NAbs targeted to conserved epitopes, we examined whether viruses from women in this cohort were recognized by HIV-1-specific MAbs with broad specificities. The maternal viruses exhibited a range of neutralization sensitivities to 2F5, VRC01, and PG9 similar to what has been reported for a large panel of diverse HIV-1 variants (4, 50, 52), suggesting that maternal viruses are not unusual in their susceptibilities to broad and potent MAbs. The neutralization sensitivities of the maternal variants were also similar to those of the viruses used to examine the breadth of the antibodies present in infant plasma. Thus, the virus panel was representative of the viruses that an infant encounters with respect to susceptibility to NAbs targeted to epitopes that are recognized by broad and potent HIV-specific MAbs.
The breadth and potency of the NAb responses acquired by the infants through maternal passive transfer were comparable to those observed in chronically infected women who were screened with a subset of the same viruses (36). This suggests efficient transfer of NAb antibodies to infants and allowed us to examine whether protection was afforded by HIV-specific NAbs at levels similar to those found in natural HIV-1 infection. Our finding that passively acquired NAbs at these levels are not broadly protective in the setting of MTCT is consistent with studies of passive antibody protection in macaques, including a recent study showing protection using a low-dose challenge model designed to more closely mirror antibody levels in natural HIV-1 infection (18). In this study and several other studies of passive transfer of HIV-1 antibodies, the macaques were exposed to a challenge virus that encodes a highly sensitive HIV-1 envelope variant (SHIVSF162) that is highly sensitive to the MAb tested (Ig-Gb12; IC50, 0.29 μg/ml [19]). Indeed, based on in vitro studies (50), more than half of all circulating viral variants studied to date would be predicted to require at least ~100-fold-more b12 to achieve a similar potency of neutralization. Thus, NAbs at this level would not be expected to protect against most of the diverse variants to which high-risk humans are exposed. Highly neutralization-sensitive variants of the type used in the macaque studies may be even more rare in the setting of MTCT, where viral evolution in the mother in response to continued antibody pressure may further increase the fraction of variants that are more resistant to maternal antibodies.
Indeed, one caveat to these experiments is the fact that there are likely to be viruses that were already selected in the mother to be less susceptible to her specific repertoire of NAbs. Because HIV-1 continually evolves to escape NAb pressure (39), most individuals generally harbor a mixture of variants that range in neutralization sensitivity. Thus, even if the mother has a broad antibody response, the more resistant variants could be transmitted despite the presence of a strong NAb response. This model is supported by studies of autologous NAb responses in the setting of MTCT, showing that viruses that are transmitted are among the more neutralization-resistant viruses in the mother (10, 51, 53). However, while the aggregate data indicate selection for more resistant variants in MTCT, there are cases where the viruses transmitted to infants are still relatively sensitive to maternal NAbs (53). Collectively, these findings suggest that there may be a threshold of NAbs required for protection, perhaps one that may also be influenced by the presence of other cofactors that affect MTCT. In some cases, the levels of HIV-1-specific NAbs found may be adequate to provide some protection, but only against highly neutralization-sensitive variants. In this context, it is perhaps not surprising that a broad and potent NAb response would not predict protection because breadth and potency against a panel of viruses do not measure the neutralization sensitivity against the most neutralization-resistant virus in the population.
Despite the unique aspects of MTCT noted above, the finding that the breadth and potency of the NAb response are not correlates of protection from HIV-1 acquisition is not specific to this setting. Similar results were observed among a small number of cases of HIV-1 superinfection (3). As with infants vertically infected with HIV-1, individuals who became superinfected did not exhibit any deficits in the breadth or potency of NAb responses compared to controls, and in some cases, they had NAbs specific for the superinfecting strain near the time of exposure (3). Collectively, these studies strongly suggest that the levels of HIV-specific NAbs found in natural HIV-1 infection, while potentially capable of providing partial protection against the most sensitive HIV-1 envelope variant, are not adequate to provide protection against HIV-1 infection with diverse, circulating strains of HIV-1 that span a range of neutralization sensitivities.
The focus of this study was on antibodies present in the infant at the time of exposure to HIV, as this is most relevant for considering the potential of antibodies elicited through immunization to protect exposed individuals. Even when the analyses were restricted to infants infected at a time when the antibody levels were highest (within 6 weeks or 6 months of life), there was no correlation between infant infection and NAb breadth and potency. However, these studies did not address the potential roles of maternal antibodies in blood, genital secretions, or breast milk or infant antibodies in the gut in impacting infant infection. It is unknown whether the repertoire of maternal antibodies is precisely reflected in the antibodies transferred to her infant. Indeed, several studies suggest that antibodies in the mother, the index case, may provide some protection (2, 7, 10, 16, 22, 45, 46, 51) even if antibodies in the infant, the exposed individual, do not protect, as suggested by this study.
We cannot rule out that there could be viruses that would predict the ability of NAbs to protect that were not included in the virus panel used here. In a Thai study of maternal antibodies and MTCT, there was evidence that the neutralizing potential against one particular regional HIV-1 strain was correlated with infant infection (2, 43). It is difficult to compare these studies directly because the prior study examined antibodies in the maternal index case, while ours focused on antibodies in the exposed infant. But these studies collectively raise the possibility that breadth and potency as currently measured using virus panels may not be ideal for predicting protective benefit; rather, there may be particular HIV-1 variants that provide a better surrogate measure of protective antibodies that remain to be identified. These studies may also suggest that our current NAb assays are not detecting responses that are relevant in transmission. Such assays measure the potential of antibodies to neutralize cell-free virus, and they do not address whether antibodies capable of neutralizing cell-associated virus may play a role. Such antibodies may be particularly important in protection in the setting of MTCT, where there is a stronger association with the levels of cell-associated virus and risk of infant infection than with cell-free virus levels (41).
Current vaccine efforts to prevent HIV-1 infections are focused on immunization of an uninfected population, and that is why the studies described here examined NAbs in the infant. One notable difference between passively transferred antibodies and those found in vaccinees is that the latter would be elicited in an immunocompetent host who had the potential to develop more potent NAb responses, particularly to a highly immunogenic vaccine. There is currently considerable interest in whether NAbs elicited by vaccination can protect exposed humans from HIV-1, but there is not yet data demonstrating that such protection is possible. In this first detailed study of the protective effect of neutralizing antibodies in infants, no benefit was observed, at least when NAb responses were measured against a virus panel. As noted above, this does not preclude a protective effect of NAbs in the index case. However, it is important to distinguish these two situations when drawing inferences for vaccine strategies, given that current efforts are not directed at immunizing an infected population to prevent viral spread. Indeed, MTCT offers a unique setting to compare the role of NAbs in protection in the index case versus in the exposed partner.
While our studies suggest that a broad and potent HIV-1 response at levels found in natural HIV-1 infection may not be adequate to provide protection from infection, they do not rule out the possibility that NAbs, if present at higher levels and/or of different specificities, could provide protection from infection. Indeed, other protective viral vaccines, such as those for hepatitis B virus (HBV) and human papillomavirus (HPV), induce NAb levels that are similar to, or even significantly higher than, those found in natural infection (6, 33, 49). At present, the NAb responses induced by current HIV-1 vaccine immunogens are at a considerably lower level than those found in chronic HIV-1 infection, where there is continual antigenic stimulation by an evolving viral quasi-species (for examples, see references 14 and 24). Thus, a major unmet challenge is to identify HIV-1 immunogens that can elicit broad NAb responses of higher potency than those elicited during natural infection.
There are promising new HIV-specific broad antibodies that have been isolated from infected individuals (50, 52), and there is evidence that some MAbs are more efficacious in passive-transfer studies than would be predicted based on in vitro neutralization measures (19). However, until there are SHIV/macaque models that better mirror the neutralization properties of circulating strains of HIV, it is hard to define the levels of antibodies needed for protection in these models. Thus, it is critical that we continue to evaluate immune correlates of protection in exposed human populations, such as infants of HIV-1-positive mothers, to define the potential for specific immune responses to protect against diverse circulating strains of HIV.
This work was supported by NIH grant R01 AI076105 to J.O. J.B.L. and C.A.B. were supported in part by NIH mentored awards K08 AI081546 and K08 AI068484, respectively.
We thank Joan Kreiss and Dorothy Mbori-Ngacha for all their efforts in the original Nairobi Breastfeeding Clinical Trial, as these were critical to the success of future derivative studies. We thank John Mascola, Xueling Wu, and the VRC team for providing the VRC01 antibody and Dennis Burton and the IAVI NAC team for providing the PG9 antibody. We thank Nicholas Provine for help and input on the neutralization assays. We especially acknowledge the women and infants who participated in the Nairobi Breastfeeding Clinical Trial and all of the study support team.
Published ahead of print on 16 March 2011.
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Researchers at the National Institute of Standards and Technology (NIST) and JILA, a joint institute of NIST and the University of Colorado (CU) at Boulder, have made the first tunable noiseless amplifier. By significantly reducing the uncertainty in delicate measurements of microwave signals, the new amplifier could boost the speed and precision of quantum computing and communications systems.
Conventional amplifiers add unwanted noise, or random fluctuations, when they measure and boost electromagnetic signals. Amplifiers that theoretically add no noise have been demonstrated before, but the JILA/NIST technology, described in an Oct. 5, 2008, advance online publication of Nature Physics,* offers better performance and is the first to be tunable, operating between 4 and 8 gigahertz, according to JILA group leader Konrad Lehnert. It is also the first amplifier of any type ever to boost signals sufficiently to overcome noise generated by the next amplifier in a series along a signal path, Lehnert says, a valuable feature for building practical systems.
Noisy amplifiers force researchers to make repeated measurements of, for example, the delicate quantum states of microwave fieldsthat is, the shape of the waves as measured in amplitude (or power) and phase (or point in time when each wave begins). The rules of quantum mechanics say that the noise in amplitude and phase cant both be zero, but the JILA/NIST amplifier exploits a loophole stipulating that if you measure and amplify only one of these parametersamplitude, in this casethen the amplifier is theoretically capable of adding no noise. In reality, the JILA/NIST amplifier adds about half the noise that would be expected from measuring both amplitude and phase.
The JILA/NIST amplifier could enable faster, more precise measurements in certain types of quantum computerswhich, if they can be built, could solve some problems considered intractable todayor quantum communicatio
|Contact: Laura Ost
National Institute of Standards and Technology (NIST)

subset: commoncrawl


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Dr Marcus Mietzner
Areas of expertise
- Government And Politics Of Asia And The Pacific 160606
- Comparative Government And Politics 160603
- Social Change 160805
- Political Science 1606
Research interests
The political role of the military in Indonesia; Indonesian political parties, particularly campaign financing issues; elections in Indonesia; comparative electoral politics in Southeast Asia.
I have been interested in the politics of Indonesia since my first visit to Jakarta as a teenager in 1986. While pursuing an MA degree at Goethe University in Frankfurt in the mid-1990s, I spent one year in Ambon to collect material for my thesis on the rebellion of the South Moluccan Republic in 1950. After graduation, I moved to the ANU to obtain my PhD. During fieldwork for a thesis on the Indonesian military, I began working for USAID in Jakarta – an engagement that would last for more than seven years. Eventually, however, I returned to academia, finishing the PhD in 2005 and starting my new position as a lecturer at the ANU in 2008. Since then, my research has primarily focused on political parties in democratic Indonesia
Projects and Grants
Grants are drawn from ARIES. To add Projects or Grants please contact your College Research Office.
- Presidential Power and its Limits in Post-Authoritarian Indonesia (Primary Investigator)
- Money Politics: Patronage, Political Networks and Electoral Dynamics in Southeast Asia (Secondary Investigator)
- Political Party Financing and Democratic Consolidation in Indonesia (Primary Investigator)


text: new slide Limited Edition Hustle View the 2016 goggle range View the Mix it Up range View the 2016 goggle range View the Mix it Up range View the range View the range Brands Latest News KTM JUNIOR NATIONALS HIT IT OVER THE FENCE For the third year running, KTM Australia's sponsorship of the Australian Junior Motocross Championships has yielded a spectacular show of professionalism, racing excitement and the promising future which lies ahead for Australian motocross. Custodians of this... 2016 SCOTT 350 Helmet range online now! Brand new for 2016 is the 350 helmet from SCOTT. Blending high end materials with leading edge design, the SCOTT 350 PRO helmets are engineered with lightweight Thermoplastic Shells, Conehead Technology™ and high-flow vent systems. The in-mold EPS liner decreases the... SCOTT young gun Grothues back on the bike After an opportunity to race the entire EMX125 championship in Europe, Caleb Grothues suffered a nasty incident at the opening round – which ultimately ruled him out of the season. With only being back on the bike for a month, Caleb made a return to racing at... 2015 KTM Ride4Kids Raises Over $70,000 For Challenge Over 250 participants and over $70,000 was raised for cancer charity Challenge which supports kids living with cancer at the 2015 KTM Ride4Kids, Australia's biggest dirt bike charity event, at Broadford on Sunday, September 13. It was a great day for motorcycle... View More Articles.Subscribe to our free e-newsletter and we will keep you informed


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January 31, 2011
Junior of the Year: Green-Beckham
Adam Gorney
Recruiting Analyst
High-profile coaches from some of college football's best programs have already found their way to Springfield (Mo.) Hillcrest to get a jumpstart on recruiting Beckham-Green, a 6-foot-6, 220-pound prospect who's been compared to Randy Moss, A.J. Green and Calvin Johnson.
Comparisons can oftentimes be overstated as people try to prop up recruits into someone they're not, but seemingly everyone who has seen Beckham-Green play raves about his advanced abilities and just how special he is on the football field.
And in basketball. And in track.
Beckham-Green is so physically impressive that comparing him to current NFL standouts is no stretch. He's built like a lean tight end but has the athleticism of the world's best wide receivers.
Huge hands. Catches everything. The complete package.
There's not much to say negative about Beckham-Green. It's difficult to imagine he's still just a junior in high school.
"He's like Kyle Prater from a couple years ago but more filled out and seems to be more physical and faster. He looks like the kind of receiver who would challenge for No. 1 in any year we've been doing this. He's that special."
The offer list is already impressive and it's growing. Alabama, Arkansas, Florida, Florida State, LSU, Miami, Michigan, Missouri, Nebraska, Notre Dame, Ohio State, Oklahoma, UCLA, USC and Wisconsin have offered Beckham-Green, who had more than 1,700 receiving yards as a junior despite playing with a first-year quarterback.
With so many programs involved, guardian and coach John Beckham is trying his best to not let things spiral out of control. He's trying to be a middleman, an intermediary between so many college coaches and Green-Beckham so the teenager doesn't lose control of the process or lose focus on that he's still so young.
"Dorial is not really focused on recruiting and what's happening right now," Beckham said. "People find that surprising but right now I'm trying to do the best I can - it's not that easy - to create a little barrier in front of him, kind of be a gatekeeper. There's just so much. I want to make sure he stays focused on academics at school and he has basketball. He's really just being a pretty typical 17-year-old right now.
"There are a lot of great schools that have offered him. He has a lot of great opportunities. You just have to find that one that fits him. It's important to find a good fit academically. That's the most important aspect of it all. The football aspect will take care of itself. If it's not a good academic fit it's not going to make sense. It doesn't matter how many BCS bowls you go to, if it's not a good academic fit for him then it's not a good fit."
On the right path
Note to college coaches: Beckham isn't just giving lip service about academics. He's quite serious about finding Green-Beckham the perfect school for football and on the school side as well.
According to reports, Green-Beckham doesn't know his father. During his youth, Green-Beckham bounced between Springfield and St. Louis, never finding stability along the way. These were nightmarish realities of having no support system and dealing with the ravages of hunger and homelessness.
It so happened that later Beckham and his family decided that it was time for Green-Beckham and his brother to move in. The maturation process continues, the molding of a teenage boy into a man while the spotlight beams bright on him.
Beckham admits that Green-Beckham struggled early this season. Local newspapers and sports talk radio covered his every move. At times, it was too much and Green-Beckham felt no matter how well he played, no matter how much he dominated, it wouldn't be enough. Then around week four, Beckham said, the star wide receiver accepted his fate.
He just played.
That's when he started to dominate.
"Guys come in here and they say he's the best they've ever seen and that's coming from people who have seen a lot of great players," Beckham said.
"I don't think he takes that very seriously. There are things he needs to work on. You can compare him to Randy Moss and A.J. Green and Julio Jones but he isn't those guys yet. He knows that. Those are good expectations but that's really not the case right now."
The potential is there though. Green-Beckham had more than 800 receiving yards and 14 touchdowns as a freshman. He had a big sophomore season when he already was becoming a national name, a superstar in the making. His junior year was exceptional even though he regularly had two defensive backs draped on him.
Rivals.com recruiting analyst Barry Every saw Green-Beckham in person this season and was clearly impressed.
"He is a huge receiver that can make a play on balls that most receivers couldn't even dream of catching and he also has the speed to be a serious deep threat while making yards after the catch," Every said. "Green-Beckham is in his own zip code as far as talent as a receiver."
Great expectations
Beckham said this next calendar year will be crucial as Green-Beckham plays his senior year of football, decides on a college and prepares to leave Springfield for the next phase in his life - transitioning from a high school star to a college freshman.
"The expectations are so high. Everybody expects him to have 200 yards receiving and four touchdowns every week and if he doesn't do that he's overrated. There are expectations from a lot of people to perform at an extremely high level all the time."
A player of his caliber commands those unreachable expectations. The better Green-Beckham plays, the more people want out of him. That has been the way of sports since time immemorial. What Green-Beckham has to focus on, if possible, is what he can control, how well he plays, how he goes about the recruiting process and decides on a future home.
It's the burden for all the great ones.
"At the beginning of this year, he really felt the pressure," Beckham said. "When the season first started, the first few weeks, there was so much hype about him with the local media and there were articles in the paper about him and they talk about him a lot on the radio. You could tell the pressure was getting to him to perform. There were coaches here every week to see him.
"After the first few weeks he settled down and accepted his role and just started playing and having fun. Ever since week four, he accepted the situation and has been great ever since."
Football Recruiting News
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BC grabs Texas receiver
Crawford back from Oregon
IMG Day 1: Top performers defense
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I presidenti 'Quarters Inn: THIS IS SAVANNAH! (SM) lodato per il suo servizio eccezionale - e sinonimo di stile storico di Savannah, l'atteggiamento, l'architettura e l'ospitalità - presidenti 'Quarters Inn è anche su Southern Living "Best Strade panoramiche del Sud" (estate 2012), VisitSouth (2013), Southern Living (2011 e 2009), Delta SKY, Viaggi Girl Magazine, breve elenco Fodor di Savannah e Best B & B & B di Charleston, e scelto le migliori Bed and Breakfast di Savannah Inn dai lettori di Savannah Magazine (2008-2013). ** Controllare breve video in PresidentsQuarters [dot] com Il premiato hotel colazione privata dispone di 16 camere e suite nel cuore di Savannah, Landmark centro del quartiere storico della Georgia eccessivamente ampi. Due palazzi adiacenti esecutivi (circa, 1855) sono state trasformate in una locanda signorile, tranquillo e intimo che coniuga comfort del 21 ° secolo con eleganza del vecchio mondo. Affacciato su Piazza Oglethorpe, presidenti storici 'Quarters Inn è acclamato come un luogo dove generali, governatori, politici e pionieri affari hanno plasmato Savannah e la storia della nazione. Ogni foresteria one-of-a-kind è chiamato ad onorare un presidente degli Stati Uniti che ha visitato Savannah durante la sua presidenza. Un cortile ombreggiato, parcheggio gratuito in loco, balconi e ingressi privati a livello della strada, accesso wireless, e vino in omaggio pomeriggio e antipasti sono solo un'infarinatura di servizi della locanda, assicurando che l'esperienza Savannah ogni ospite è rilassante e straordinaria . A pochi passi da ristoranti di Savannah preferiti, negozi e il quartiere dei teatri.
The Presidents' Quarters, an Historic Savannah Inn Video: THE PRESIDENTS' QUARTERS INN: THIS IS SAVANNAH! (SM) Praised for its outstanding service -- and synonymous with historic Savannah's style, attitude, architecture and hospitality -- The Presidents' Quarters Inn is featured in Southern Living (2011 & 2009), Delta SKY (2007), Travel Girl Magazine (2008), Fodor's short list of Savannah and Charleston's Best B&Bs & Inns (2007), and was chosen Savannah's Best Bed and Breakfast Inn by the readers of Savannah Magazine (2009 and 2008.) The award-winning private breakfast hotel features 16 overly-spacious rooms and suites in the heart of Savannah, Georgia's downtown Landmark Historic District. Two adjoining executive mansions (ca. 1855) have been transformed into a stately, restful, and intimate inn that marries 21st century amenities with old world elegance. Overlooking Oglethorpe Square, historic Presidents' Quarters Inn is acclaimed as a place where generals, governors, politicians and business pioneers have shaped Savannah's and the nation's history. Each one-of-a-kind guest quarters is named to honor a U.S. President who visited Savannah during his presidency. A shaded courtyard, free on-site parking, balconies and private entrances at street level, wireless access, and complimentary afternoon wine and hors d'oeuvres are just a smattering of the inn's amenities, assuring that every guest's Savannah experience is relaxing and extraordinary. A short walk to Savannah's favorite restaurants, shopping, and the theater district.
Una Carta Regalo BedandBreakfast.com è ideale per chi ha tanto bisogno di relax. Le carte sono unicamente accettate nei B&B nordamericani.
Valore della struttura31 Recensioni
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su gennaio 13, 2015
We come to Presidents' Quarters every year for a "getaway." It's hard to pick just one best aspect about this B&B since everything is outstanding! The front desk help is always there to "help" you, in addition to being very personable. In talking with the staff, there is a very low turnover rate among the employees. We've seen the same front desk staff for years and they remember us as well. They're not going through the motions. You truly feel special when you interact with the staff!
The late afternoon appetizers along with the morning breakfasts are extremely tasty, as well as creative!
The location also can't be beat, located in the beautiful, shady historic district.
We've tried other B&B's in the area, but we keep coming back to the Presidents' Quarters without even blinking. Truly a gem of Savannah!
su maggio 24, 2014
Short visit on our way home to New York. We have stayed in several Savannah Inns but this one is by far the best. Wonderful staff, perfect location, delicious breakfast and very nice quality wines with the hors d'oeuvre time. Add parking and you tell me why you would stay anywhere else?
su settembre 01, 2013
We stayed at Presidents Quarters on a recent whirlwind trip to the southeast. We love bed and breakfasts and small inns and stay in them as often as we can. We had much to choose from in Savannah but this inn is spectacular. Rooms, food, staff location, are all excellent. Special thanks to Anna for her delicious Banana Foster French Toast. The best I've ever had.
The staff are amazing and the location with a parking lot can't be beat.
su febbraio 24, 2013
My wife, daughter and I spend a wonderful weekend here in February. The staff could not be more helpful and accommodating. Our room, the George Washington Suite was lovely and suited us perfectly. Breakfast was delicious, especially the breakfast burritos served with a beautiful fruit cup.Wine and hors d'oeuvres in the early evening was a nice touch before we left for the evening. The Presidents' Quarters is located in the heart of the historic district and we could walk to everything from the inn. We will return to Savannah and we won't consider staying anywhere else!
su febbraio 10, 2013
Our first visit to Savannah and staying at The Presidents' Quarters made it a special treat. The staff was exceptionally friendly and accommodating,and wete extremely helpful in recommending things to do as well as great restaurants. The overall atmosphere of the Inn was warm and welcoming and the rooms were clean, spacious and inviting. We will definitely return to this charming Southern treat.
su dicembre 12, 2012
Our stay was very relaxing and enjoyable. The innkeepers were very nice and helpful. The location was perfect for venturing out to see the beautiful sights of Savannah. The breakfast was good and the service was excellent. The rooms were very clean and well furnished. We stayed in one of the top floor suits and felt very comfortable.
su ottobre 03, 2012
A five star, wonderful place to stay. Our room (Eisenhower suite) was gorgeous, roomy, and had a great balcony. We could not recommend this Bed & Breakfast enough. The entire staff, from the owner, kitchen folks and housekeepers was extraordinarily nice, helpful, and friendly. My wife and I are both working people, yet we were treated like royalty. Nice to wake up early, and see that everyone working here had a great sense of humor, and went way out of their way to accommodate a couple on their honeymoon. I did my research to find the perfect place, and this was certainly it. We have no regrets picking the President's Quarters for our honeymoon. It is centrally located in the historic district of Old Town Savannah- parked the car and left it for a week. Everything one would want to do in this city is easily within walking distance. We are already planning an anniversary trip returning here.
Pam and Keith
su settembre 20, 2012
We just passed through, quick trip, short stay, but well worth it! We are a family of four with two boys under three years old...in other words...we are a handful! The room was ideal and the curious staff even offered us other open rooms for our choosing. The best way to describe the staff is flexible. Bigger room or bigger bed? Yogurt or pancakes? Or yogurt and pancakes? Breakfast early or late? How about late-ish? Bottom line, you made a mistake if you don't stay here.
su luglio 28, 2012
My family enjoyed the initial leg of our Fourth of July holiday at the President's Inn. The service and accommodations were outstanding. The breakfast and cocktail hours were delightful as well. And, the entire staff was warm and friendly, especially April, our server at breakfast time. And, the location couldn't have been more convenient. We parked our car when we first arrived and didn't both with it again until we left. We couldnt' recommend this inn any more highly.
su luglio 02, 2012
We loved the room (103), the Johnson Room. We arrived and were immediately greeted and treated like we have been there before. The room was large and had it's own AC which was a huge bonus because Savannah was brutally hot. The staff left out some wine and snacks for us to have before we went to dinner. When we returned from dinner our bed was turned down and ready for sleeping. Additionally, we had some sweets on our pillow and some port was available in the lobby. Every morning you have a choice of a hot breakfast or continental. The breakfasts were good, and even though we've had better food at other places it was easily comparable to having breakfast out at a restaurant. You cannot beat the location at this inn. We parked our car and did all of our Savannah sightseeing by foot. The staff recommended some great places to eat as well. Moreover, the staff asked our interests and gave us so many options that we could not do all of them in one trip. The inn is a bit more expensive but the location, comfort, and level of quality make everything worth it. You may not want to sleep on the bottom floor if you are noise sensitive as you can hear cars and people if they are being loud. The flip side to this is you can also hear all the horses and carriages as they give tours. It was cool.
Vedi Altre Recensioni
Piccolo Paese,
Savannah, GA (SAV) 17 miles
Da I-16, prendere Montgomery Street Exit, quindi svoltare a destra Oglethorpe Avenue. Girare a sinistra su Abercorn Street, poi subito a destra su York Street. The Presidents 'Quarters offre in omaggio comodo parcheggio in loco / privato, con ingresso off York Street.
Shopping Antiquariato,
Gallerie d'arte,
Cene da gourmet,
Interessi Storici,
Musica dal vivo,
Zona Naturale,
Il più grande quartiere storico in America,
Area Picnic,
Servizi religiosi,
Bed and Breakfast
Computer, Fotocopiatrici, Dispositivo Fax, Attrezzature matrimoni ,
Hospitality suite sono dotate di soppalco camera da letto + mobile bar
Aria condizionata, Sveglia , Accappatoi, CD player, Scrivania, Camino, Frigorifero, Asciugacapelli, Jacuzzi, Accesso a internet , Ferro da stiro, Ingresso privato, Radio, TV via cavo/satellite, TV, Telefono, Servizio di Rimbocco Coperte, Angolo bar, Wi-Fi
Noleggio bici, Biliardo, Osservazione Uccelli, Pesca, Golf, Escursioni, Kayak, Bambini musei d'arte & play interattivi, Shopping, Scenari, Campi da tennis
Jane Sales, Executive Innkeeper
Plus continentale
, On Advance Request
Delizioso casalingo Granola
$150 a notte
Proprietari: Jane Sales, Executive Innkeeper
Ospiti: 2
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Thackeray the Sentimental Sceptic
Bruce, Donald, Contemporary Review
OPPRESSED as he was by his sense of a lost past and a solitary present spent in either defeat or disillusion, W. M. Thackeray was readily attracted by whatever was stable in an age of uncertainty. Although there is little distinct landscape in his novels, and even in his travel books his response to scenery is largely anecdotal, his heart warms to the substantially unchanging streets, each having its own social tradition, of such places as London, Brighton and Paris. Like his cockney excursionist in Vanity Fair, Thackeray is 'a lover of human nature rather than of prospects of any kind'.(1) In spite of that, Thackeray remains a poet and a scholar of the urban scene. He is acute in the distinctions implied by different London addresses: between Becky Sharp's Brompton and Amelia Sedley's Fulham, geographically adjoining suburbs, but socially quite disparate. Nobody understood better than Thackeray the dividing line drawn through London by Regent Street and its continuations. To the west of the line lived the four or five hundred people who constituted fashionable society in 1847.(2)
The opposition of western to eastern London is as marked in Thackeray's novels as it is in Restoration Comedy. Like the hero of a play by Congreve, Rawdon Crawley exclaims of George Osborne, whom he is modishly bilking at cards, 'Hang these City fellows, they must bleed; and I've not done with him yet, I can tell you' (Vanity Fair, chapter 14). Major Pendennis, although he has lived in London for much of his life, cannot find his way to a district so unfashionable as the Temple and, when he is forced to go there, sends his manservant to plot a route for him (Pendennis, chapter 29).
Thackeray never moved into patrician Mayfair, although he did reside immediately north of it in Albion Street and a little south of it in Jermyn Street; which is appropriate to his position as a social commentator. He observes Mayfair from a distance, not as an admirer but as a spy. He belongs to neither high life nor to low. As he claims, he 'is just as familiar with Newgate as with the palaces of our revered aristocracy, and has seen the outside of both' (Vanity Fair, chapter 6). He settled in the remote purlieus of Kensington, haunted as it was by the ghosts of the late Stuarts who had cast such a spell over him. It is true that he is more in sympathy, although it is a teasing sympathy, with Major Pendennis and Rawdon Crawley than with James Yellowplush or the Mosses of Wardour Street. He identifies himself with Henry Esmond and Arthur Pendennis, certainly; but also with the humbly born artist John James Ridley, in whose person he once planned to write a novel (Ray II,p.265). Thackeray's mightiest aristocrat, the Marquis of Steyne, also lives outside Mayfair, in one of the squares north of Oxford Street, as if as scornful as Thackeray himself of such foolish demarcations. He and Thackeray are wilful outsiders in their contempt for mere fashion.
London was important to Thackeray as providing a firm setting, at least, for his flitting mutabilities: London as Colonel Newcome witnessed it between two disappointed retreats to India, where he was supporting London's opulence, on a summer evening at five o'clock:
Horses under the charge of men in red jackets are pacing up and down St. James's Street. Cabmen on the stand are regaling with beer. Gentlemen with grooms behind them pass towards the Park (Newcomes, chapter 6).
Mere place-names become evocative. The impoverished paterfamilias vacates his house in Harley Street and subsides into lodgings in Pentonville or Kensington, yet finds that his neighbours respect him more in those outlying districts: 'If I cannot be first in Piccadilly, let me try Hatton Garden, and see whether I cannot lead the ton there' (Newcomes, chapter 9). But these traditions and associations do not last forever. Certain districts become fashionable or unfashionable. Thackeray contemplates the decline, in Victorian times, of such quarters as Portland Place and Bedford Square, and compares their downfall to that of conquered cities in India -- Agra, Benares and Lucknow -- where shahs and sultans once ruled (Newcomes, chapter 8). …