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Biomedical subjects

P Mooij

Publications and source records attributed to P Mooij.

18 recordsLinked to original sources
PubMed2001

Protection from secondary human immunodeficiency virus type 1 infection in chimpanzees suggests the importance of antigenic boosting and a possible role for cytotoxic T cells.

Recent evidence suggests a much higher prevalence of human immunodeficiency virus type 1 (HIV-1) recombinants than previously anticipated. These recombinants arise from secondary HIV infections in individuals already infected with the virus. It remains unclear why some individuals acquire secondary HIV-1 infections and others do not. To address this question, a study was undertaken of a small cohort of chimpanzees with well-defined HIV-1 infection. After exposure to an infectious dose of heterologous primary isolate, 4 of 8 HIV-1 seropositive chimpanzees resisted secondary infection, whereas 2 naive controls became readily infected. Only animals who were immunologically boosted were protected. Protection from heterologous secondary exposure appeared to be related to the repertoire of the cytolytic CD8(+) T cell responses to HIV-1. Data suggested that immunologic boosting by HIV-1 antigens or exposure to subinfectious doses of virus may be important events in sustaining sufficient immunity to prevent secondary infections from occurring.

AIDS Vaccines↗
PubMed2000

Evidence for viral virulence as a predominant factor limiting human immunodeficiency virus vaccine efficacy.

Current strategies in human immunodeficiency virus type 1 (HIV-1) vaccine development are often based on the production of different vaccine antigens according to particular genetic clades of HIV-1 variants. To determine if virus virulence or genetic distance had a greater impact on HIV-1 vaccine efficacy, we designed a series of heterologous chimeric simian/human immunodeficiency virus (SHIV) challenge experiments in HIV-1 subunit-vaccinated rhesus macaques. Of a total of 22 animals, 10 nonimmunized animals served as controls; the remainder were vaccinated with the CCR5 binding envelope of HIV-1(W6.1D). In the first study, heterologous challenge included two nonpathogenic SHIV chimeras encoding the envelopes of the divergent clade B HIV-1(han2) and HIV-1(sf13) strains. In the second study, all immunized animals were rechallenged with SHIV(89. 6p), a virus closely related to the vaccine strain but highly virulent. Protection from either of the divergent SHIV(sf13) or SHIV(han2) challenges was demonstrated in the majority of the vaccinated animals. In contrast, upon challenge with the more related but virulent SHIV(89.6p), protection was achieved in only one of the previously protected vaccinees. A secondary but beneficial effect of immunization on virus load and CD4(+) T-cell counts was observed despite failure to protect from infection. In addition to revealing different levels of protective immunity, these results suggest the importance of developing vaccine strategies capable of protecting from particularly virulent variants of HIV-1.

AIDS Vaccines↗
PubMed1999

Conserved CTL epitopes shared between HIV-infected human long-term survivors and chimpanzees.

Certain HIV-1 infected humans that do not progress to AIDS have been documented to share particular MHC class I alleles that appear to correlate with long-term survival. HIV-1-infected chimpanzees are relatively resistant to progression to AIDS. Out of a group of 10 chimpanzees with CTL activity and nonprogressive HIV-1 infection, 2 animals with prominent cytolytic CD3+CD8+ T cell responses to HIV-1 Ags were studied in detail. Characterization of these CTL revealed that they contained the granzymes A and B, T cell intracellular Ag-1, and perforin and induced calcium-dependent cytolysis that correlated with the presence of apoptotic nuclei in target cells. These CTL responses were directed against two gagpeptides, which were found to be identical to previously described epitopes recognized in the context of HLA-B27 and HLA-B57 molecules. The latter two restriction elements occur with increased frequency in human long-term survivor cohorts. Phylogenetic comparisons revealed that the chimpanzee restriction elements, Patr-B*02and -B*03, described here do not show any obvious similarity with the HLA-B*27 and -B*57 alleles, suggesting that CTL responses to HIV-1 in distinct primate species may be controlled by different types of HLA-B-like molecules. The CTL responses in these two chimpanzees are directed, however, against highly conserved epitopes mapping across the majority of HIV-1 clades.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Differential cytotoxic T-lymphocyte (CTL) responses in HIV-1 immunised sibling chimpanzees with shared MHC haplotypes.

Cell mediated immune responses to HIV-1 and CTL responses in particular differ dramatically in infected individuals. This may largely be influenced by the immunogenetic differences of different individuals such as those encoded by the MHC. These differences may be difficult to dissect due to the immunosuppressive nature of HIV-1 infection itself. In order to reduce the variables associated with effects of the virus, one recombinant viral antigen was chosen from a particular HIV-1 variant (rgp120 of the clinical isolate HIV-1w6.1D). To minimise differences between outbred hosts, we chose two sibling chimpanzees from which the family pedigree and genetic segregation with respect to polymorphic MHC molecules was known. Immunisation induced strong antigen specific antibody and T-helper immune responses. The magnitude and persistence of the humoral and T-helper immune responses were comparable in both chimpanzees. However, CTL responses were only observed in one sibling. These responses were subsequently mapped to several distinct epitopes. The CTL response to the immunodominant epitope was found to be presented in the context of a MHC molecule which was shared by both siblings. The absence of a CTL response in the other sibling is not yet understood, but could not be attributed to MHC alleles that were not shared by these two chimpanzees. These findings suggest that other polymorphic immunoregulatory mechanisms such as those involved in antigen processing and presentation influence host CTL responses to HIV-1.

Animals↗
PubMed1999

HIV-1 vaccine-induced immune responses which correlate with protection from SHIV infection: compiled preclinical efficacy data from trials with ten different HIV-1 vaccine candidates.

The specific immune mechanisms necessary and/or sufficient to elicit HIV-vaccine protection remain undefined. Utilising the SHIV rhesus macaque model the immunogenicity as well as the efficacy of ten different HIV-1 vaccine candidates was evaluated. Comparison of the immune responses induced, with the ability of the vaccine to protect from SHIV infection provided a means to determine which type of immune responses were necessary for protection. Vaccine candidates included VLPs, DNA, subunit protein with novel adjuvant formulations, ISCOMs and pox-virus vectors. Protection from SHIV infection was achieved in approximately half of the animals which received a primary intravenous cell-free challenge. The presence of CTL in the absence of other effector responses did not correlate with protection from this route and type of challenge. Virus neutralising antibodies (Nab) appeared to be necessary but alone were insufficient for protection. If Ag-specific IFN-gamma and/or IL-4 as well as lymphoproliferative (LP) responses were found with the lack of a detectable IL-2 response, then protection was not observed. Immunity correlated with the magnitude of Nab responses, beta-chemokines and as well as balanced, qualitative T-helper responses.

AIDS Vaccines↗
PubMed1999

Comparison of immunity generated by nucleic acid-, MF59-, and ISCOM-formulated human immunodeficiency virus type 1 vaccines in Rhesus macaques: evidence for viral clearance.

The kinetics of T-helper immune responses generated in 16 mature outbred rhesus monkeys (Macaca mulatta) within a 10-month period by three different human immunodeficiency virus type 1 (HIV-1) vaccine strategies were compared. Immune responses to monomeric recombinant gp120SF2 (rgp120) when the protein was expressed in vivo by DNA immunization or when it was delivered as a subunit protein vaccine formulated either with the MF59 adjuvant or by incorporation into immune-stimulating complexes (ISCOMs) were compared. Virus-neutralizing antibodies (NA) against HIV-1SF2 reached similar titers in the two rgp120SF2 protein-immunized groups, but the responses showed different kinetics, while NA were delayed and their levels were low in the DNA-immunized animals. Antigen-specific gamma interferon (IFN-gamma) T-helper (type 1-like) responses were detected in the DNA-immunized group, but only after the fourth immunization, and the rgp120/MF59 group generated both IFN-gamma and interleukin-4 (IL-4) (type 2-like) responses that appeared after the third immunization. In contrast, rgp120/ISCOM-immunized animals rapidly developed marked IL-2, IFN-gamma (type 1-like), and IL-4 responses that peaked after the second immunization. To determine which type of immune responses correlated with protection from infection, all animals were challenged intravenously with 50 50% infective doses of a rhesus cell-propagated, in vivo-titrated stock of a chimeric simian immunodeficiency virus-HIVSF13 construct. Protection was observed in the two groups receiving the rgp120 subunit vaccines. Half of the animals in the ISCOM group were completely protected from infection. In other subunit vaccinees there was evidence by multiple assays that virus detected at 2 weeks postchallenge was effectively cleared. Early induction of potent type 1- as well as type 2-like T-helper responses induced the most-effective immunity.

AIDS Vaccines↗
PubMed1998

A clinically relevant HIV-1 subunit vaccine protects rhesus macaques from in vivo passaged simian-human immunodeficiency virus infection.

OBJECTIVES: To investigate whether immunization with recombinant HIV-1 envelope protein derived from a clinical isolate could protect macaques from infection with an in vivo passaged chimeric simian-human immunodeficiency virus (SHIV). DESIGN AND METHODS: A total of 16 animals were studied from which three groups of four animals were immunized with vaccine formulations of the CC-chemokine receptor-5-binding recombinant gp120 of HIV-1W6.1D. Four weeks after the last immunization, all 16 animals were intravenously challenged with in vivo passaged SHIV derived from the same HIV-1 group B clinical isolate (W6.1D) as the vaccines. RESULTS: Vaccine protection from infection was demonstrated in 10 out of 12 macaques immunized with recombinant gp120. Complete protection from infection was achieved with all of the animals that received the SBAS2-W6.1D formulation, a potent inducer of both T-cell and humoral immune responses. Partial protection was achieved with SBAS1-W6.1D, a formulation based on immunomodulators known to induce T-cell responses in humans. In vaccinated animals that were infected, virus load was reduced and infection was delayed. CONCLUSIONS: In a relatively large number of primates, vaccine efficacy was demonstrated with a clinically relevant HIV-1 vaccine. These results reveal that it is possible to induce sterilizing immunity sufficient to protect from infection with SHIV which was passaged multiple times in vivo. Our findings have implications for current HIV-1 clinical vaccine trials and ongoing efforts to develop safe prophylactic AIDS vaccines.

AIDS Vaccines↗
PubMed1994

Effect of thyroid hormones and other iodinated compounds on the transition of monocytes into veiled/dendritic cells: role of granulocyte-macrophage colony-stimulating factor, tumour-necrosis factor-alpha and interleukin-6.

Stimulation of human peripheral blood monocytes with the thyroid hormones tri-iodothyronine (T3) and thyroxine (T4) enhanced their ability to mature into cytologically and functionally characteristic veiled/dendritic cells. Veiled/dendritic cell transition induced by T3 and T4 was dependent on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) in the culture, since the addition of antibodies specific for GM-CSF, TNF alpha and IL-6 to the culture system had blocking effects. The addition of antibodies to macrophage colony-stimulating factor and IL-1 had no effects. Contaminating T cells and B cells did not contribute to the transition of monocytes to veiled/dendritic cells, and it is therefore likely that the GM-CSF, TNF alpha and IL-6 produced in the culture system were derived from the monocytes themselves. Stimulation of the blood monocytes with an optimal concentration of metrizamide (14.5%), reverse T3 (rT3; 2 x 10(-10) M) or highly iodinated thyroglobulin (Tg; 2 x 10(-11) M) also resulted in an increased transition of monocytes to veiled/dendritic cells, but to a lesser extent in comparison with the thyroid hormones (T3, 31 +/- 6% and T4, 25 +/- 5% vs rT3, 22 +/- 8% and Tg with an iodination grade of 0.37%: 20 +/- 4% veiled/dendritic cells). Administration of anti-GM-CSF, anti-TNF alpha and anti-IL-6 to the culture system also had blocking effects on the transition from monocytes to veiled/dendritic cells induced by the iodinated compounds. The mechanisms by which such iodinated compounds act on the monocyte to veiled/dendritic cell transition can only be speculated on (interference H2O2-generating system?).

Antibodies, Monoclonal↗
PubMed1994

A high iodine intake in Wistar rats results in the development of a thyroid-associated ectopic thymic tissue and is accompanied by a low thyroid autoimmune reactivity.

Evidence is accumulating that dietary iodine intake is an important modulator of autoimmune thyroid reactions. To study this role of iodine intake further, female Wistar rats were kept on an enriched iodine diet (EID, iodine intake 100 micrograms iodine/day) for a period of up to 18 weeks. Control rats were either on a normal iodine diet (NID, iodine intake 7 micrograms iodine/day) or a low iodine diet (LID, 2 days of 1% KClO4 followed by iodine-deficient drinking water/pellets). During the first 6 weeks of the EID rats developed a thyroid-associated ectopic thymic tissue (50-57% of the animals on EID versus 7-14% of NID rats and 0% of LID rats). This thyroid-associated ectopic thymic tissue showed a similar histology (cortex and medulla) and a similar marker pattern as normal rat thymus concerning TdT expression (positive cells in the cortex) and CD4/CD8 positivity (double-positive cells in the cortex, single-positive cells in the medulla). The excessive iodine diet also resulted in a lowered thyroid autoimmune reactivity as compared to the NID and LID, viz. (1) in a lower incidence of anti-colloid antibodies in serum (12.5% positivity in EID rats versus 36% in NID and 60% in LID rats at 18 weeks) and (2) lower numbers of intrathyroidal lymphoid cells, viz. lower numbers of dendritic cells and lower numbers of CD4 and CD8 positive lymphocytes. It is hypothesized that the development of the thyroid-associated ectopic thymic tissue in the EID rats is related to their low thyroid autoimmune responsiveness; the tissue might play a role in tolerance induction to thyroidal autoantigens.

Animals↗
PubMed1993

An excess of dietary iodine accelerates the development of a thyroid-associated lymphoid tissue in autoimmune prone BB rats.

Previous studies have shown that dietary iodine enhances the severity and incidence of focal thyroiditis in autoimmune BB rats and OS chickens. However, which lymphoid cells are involved in the development of the iodine-induced focal thyroiditis and what the consequences are for the anticolloid antibody production have not been studied in detail. We therefore performed a study in which 3-week-old female BB rats were kept on either an enriched iodine diet (EID; iodine intake, 100 micrograms iodine/day) or a normal iodine diet (NID; iodine intake, 7 micrograms iodine/day) for a period of 18 weeks. The development of the focal thyroiditis was immunohistologically studied. Immunohistological data were compared to the thyroid hormone status and anti-colloid antibody production. Our data confirm that a high dietary iodine intake results in an accelerated development of the focal lymphoid cell infiltrates in the thyroid of the BB rat. After 12-18 weeks of an EID 50% of the BB rats developed these infiltrates. Our data additionally show that: (a) the process starts with increases in the number of infiltrating MHC class II-positive dendritic cells and a clustering of these cells with T cells, B cells, and some macrophages and (b) the focal infiltrates are highly organized and consist of central B cell follicle-like structures surrounded by rims and areas of T cells. The architecture of the focal thyroiditis is hence very similar to mucosa-associated lymphoid tissue and secondary lymphoid organs (spleen and lymph node). Only minor signs of thyrocyte destruction were observed. We therefore consider the term "thyroiditis" as inappropriate and prefer the term "thyroid-associated lymphoid tissue." Since the thyroiditis component was small, it is also not surprising that the BB rats on the EID remained euthyroid. The presence of the thyroid-associated lymphoid tissue in the BB rats was positively correlated to the presence of anti-colloid antibody in the serum of the BB rats. We speculate that the dietary iodine might have direct effects on cells of the immune system or on cells forming the microenvironment of lymphoid tissue (reticulum cells). A role for highly iodinated thyroglobulin in the accelerated development of thyroid-associated lymphoid tissue is also possible.

Animals↗
PubMed1993

Expression of various MHC class II molecules and of intracellular adhesion molecule-1 (ICAM-1) on focal clusters of dendritic cells in iodine deficiency goitres.

Thyroid sections from 18 consecutive euthyroid patients undergoing surgery for iodine deficiency goitre were investigated by means of immunohistochemistry and immunofluorescence, evaluating the expression of MHC class II antigens (HLA-DR, -DP, -DQ, and RFD1) and intercellular adhesion molecule-1 on the formerly described clusters of dendritic cells, as well as on thyrocytes. Eleven of 18 iodine deficiency goitres contained clusters of dendritic cells. These clusters appeared to express only HLA-DR in two cases; in nine of 12 cases they showed a differential expression of class II molecules in the following frequency: HLA-DR > DQ and/or -DP > RFD1. These dendritic cells also were ICAM-1+. In four of 18 iodine deficiency goitres, thyroid epithelial cells showed MHC class II expression in several combinations, but were ICAM-1-. In normal thyroids and in nodular goitres from inhabitants of the endemic area not having an actual iodine deficiency, only sparse clusters of dendritic cells were found; these cells were only HLA-DR+. Follicle lining cells were negative for the MHC class II molecules. In normal thyroids from an area with sufficient iodine supply, no clusters of dendritic cells were seen. The few dendritic cells observed were lying isolated in the interstitium and only positive for HLA-DR and ICAM-1; epithelial cells were negative for the studied markers. These data show clusters of dendritic cells in thyroids of inhabitants of an endemic area. When goitre is accompanied by iodine deficiency at the moment of operation, there appears to be activation of these dendritic cells and of thyroid epithelial cells.

Adult↗
PubMed1993

Iodine deficiency induces thyroid autoimmune reactivity in Wistar rats.

The last 2 decades it has become clear that iodine deficiency has a modulating effect on the thyroid autoimmune response in humans. Also, in animals that spontaneously develop autoimmune thyroid disease, evidence is accumulating that a low iodine intake can modulate thyroid autoimmune reactivity. However, it is still not clear what the effect of a low iodine intake on thyroid autoimmune reactivity is in normal nonautoimmune animals. To study the relationship of a dietary low iodine intake on the thyroid autoimmune reactivity in nonautoimmune animals, normal Wistar rats (female) were kept on an enriched iodine diet (daily iodine intake of 100 micrograms iodine), a "for our area normal" (conventional) diet (COD; daily iodine intake of 7 micrograms iodine), a low iodine diet (LID; 2 days of 1% KCLO4, followed by iodine-deficient drinking water/pellets), or an extremely low iodine diet (LID+; 1% KCLO4 continuously in the drinking water and iodine-deficient pellets). The enriched iodine diet rats were euthyroid (T3, approximately 8 nM/liter: T4, approximately 50 nM/liter; TSH, approximately 2 ng/ml), had a normal thyroid weight (approximately 12.5 mg), and showed only minimal signs of local thyroid immune reactivity; low numbers of intrathyroidal dendritic cells (DC; approximately 35 DC/mm2), CD4+ cells (approximately 2 cells/mm2), and CD8+ cells (approximately 2.5 cells/mm2) were found in combination with low anticolloid antibody production (incidence of positive animals, 12.5%). The COD resulted in a normal thyroid function. The rats were euthyroid (range of T3, 1.6-1.2 nM/liter; T4, approximately 50 nM/liter; TSH, approximately 2 ng/ml) and had a normal thyroid weight (approximately 12.5 mg). However, some signs of thyroid autoimmune reactivity were found [number of intrathyroidal DC, approximately 40/mm2; approximately 3 CD4-positive (CD+) cells/mm2; approximately 3 CD8+ cells/mm2; together with a 30% incidence of anticolloid antibodies]. The LID and LID+ not only induced goiter formation [thyroid weight, 27.3 +/- 4.2 mg (mean +/- SD) after 12 weeks of LID and 38.4 +/- 5.3 mg after 4 weeks of LID+] and low production of T4 by the thyroid [28 +/- 3 nM/liter (mean +/- SD)] after 12 weeks of LID and 14 +/- 3 nM/liter after 2 weeks of LID+], but also induced various signs of thyroid autoimmune reactivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Autoimmune thyroid disease.

A considerable proportion of the thyroid diseases is due to aberrant immune reactions toward thyroid antigens. Autoreactivity is considered to be a normal process controlled by several suppressor mechanisms. Malfunction of these suppressor mechanisms may result in autoimmune disease. Mechanisms of self-tolerance, defects in autoimmune disease, thyroid autoantibodies, thyroid autoreactive T cells, several thyroid autoimmune diseases, and the role of iodine in thyroid autoimmune reactivity are addressed.

Autoantibodies↗
PubMed1992

Interactions between the immune system and the thyroid. Regulatory networks in health and disease.

Hashimoto's thyroiditis, primary myxedema and Graves' disease are thyroid disease that are due to autoimmune reactions towards thyroidal antigens such as thyroid peroxidase (TPO), thyroglobulin (Tg) and the TSH receptor. Thyrocyte destruction in Hashimoto's thyroiditis and primary myxedema is caused by TPO- and Tg-specific lymphocytes and autoantibodies, thyrocyte stimulation in Graves' disease is caused by antibodies stimulating the TSH receptor, thyroid atrophy in primary myxedema is caused by antibodies blocking the TSH receptor, or a yet unknown thyroid growth receptor. The above listed thyroid autoimmune diseases are familial (genetically determined), and due to defects in the immunoregulatory mechanisms that should normally control excessive thyroid autoimmune reactivity. This control towards thyroidal antigens (tolerance) can be broken by professional antigen presenting cells, such as the dendritic cells. It is now known that thyroid autoimmune diseases are indeed initiated by dendritic cells: dendritic cells are present in low number in normal thyroids, but accumulate very early in thyroids that are later affected by thyroid autoimmune disease. Dendritic cells are also present in the normal anterior pituitary and in this gland they are known as the (folliculo) stellate cells, the regulators of growth and function of the surrounding pituitary-endocrine cells. It is discussed whether the influx and clustering of dendritic cells in the thyroid observed during early autoimmune thyroid disease is meant for the regulation of growth and function of the thyrocytes thus linking a putative early endocrine disturbance to the initiation of thyroid autoimmune disease.

Autoimmunity↗
PubMed1990

Thyroid growth stimulating immunoglobulins in sporadic and endemic colloid goitre.

Several methods have been described to measure immunoglobulins stimulating the growth of thyroid cells in vitro, the so called Thyroid Growth stimulating Immunoglobulins (TGI). The methods make use of either Ig-stimulated guinea pig thyroid (organ) cultures (the cytochemical bioassays; growth is measured via Feulgen-densitometry or pentose shunt analysis), the culture of Ig-stimulated rat or porcine thyroid follicles (growth is measured via 3H-thymidine incorporation), or of Ig-stimulated rat FRTL-5 cells (growth is measured via 3H-thymidine incorporation, or counting the number of mitoses in arrest). The various methods have now been validated: (a) the data obtained with TGI preparations in the Feulgen Cytochemical Bioassay (CBA's) correlate well with those obtained in the FRTL-5 mitosis arrest assay with the same TGI preparations, (b) the growth stimulation can not be ascribed to hormonal contaminations of the used Ig preparations, since protein A-sepharose purified IgG is active in the assays and since anti human IgG's neutralize the growth stimulating effects of the preparations. Using the assays TGI has been found positive in goitrous Graves patients, in sporadic goitre patients and in endemic goitre patients. Particularly, patients complaning of recurrent goitre after thyroidectomy or with recent goitre growth are TGI positive. TGI occurs in sporadic goitre in the absence of TSH-receptor antibodies. The autoimmune-prone animal model of the BB rat also proved to be TGI-positive; the animal shows an increased thyroid glandular weight. Both the histomorphology of human goitres as well as the goitre of the BB rat indicate that the dendritic cell plays a prominent role in initiating the thyroid autoimmune reaction.

Animals↗
PubMedDate not supplied

Efforts to broaden HIV-1-specific immunity by boosting with heterologous peptides or envelope protein and the influence of prior exposure to virus.

In two previous studies, we have demonstrated the successful protection of human immunodeficiency virus type 1 (HIV-1)-vaccinated rhesus macaques from challenge with SHIV(SF13) with envelop immunogens derived from the closely related HIV-1(SF2) strain. Here we report on two follow-up studies in which we aimed to broaden immunity in order to elicit protection from a more diverse heterologous challenge with SHIV(SF33). In the first study, animals were boosted once with HIV-1(SF33) V2 and V3 peptides that were cross-linked to influenza immune-stimulating complexes (ISCOMs). In the second study, monkeys were boosted twice at 12-week intervals, using a heterologous recombinant gp120 derived from HIV-1(SF33) that was either incorporated into ISCOMs or mixed with the MF59 adjuvant. In both studies, the animals were challenged with 50 monkey infectious doses of SHIV(SF33) 4 weeks after the final boost. All controls became readily infected with the heterologous challenge virus SHIV(SF33). Neither boosting with heterologous SF33 peptides or gp120 afforded protection from infection to SF2-vaccinated animals that had previously resisted SHIV(SF13) challenge. These results demonstrate the importance of developing vaccine strategies that are capable of generating broad immune responses early in the immunization protocol. Furthermore, these findings may illustrate the potential pitfalls of early antigenic sin.

AIDS Vaccines↗