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Feedback that young children receive from others can affect their emotions and emerging self-views. The current experiment tested the effect of negative content (criticism) and negative tone (hostile) of the feedback on children’s affect, self-evaluations, and attributions. We also explored whether maternal history of depression and children’s temperament moderated these relations. Participants were 152 mothers and children (48% girls) aged 4 and 5 years (M = 61.6 months, SD = 6.83). The task involved three scenarios enacted by dolls; a child doll made something (e.g., picture, house, numbers) that had a mistake (e.g., no windows on the house) and proudly showed it to the mother doll, who then gave feedback (standardized, audio recorded) to the child. Children were randomized to one of four maternal feedback conditions: negative or neutral content in either a negative or neutral tone. Negative content (criticism) produced significantly more negative affect and lower self-evaluations than neutral content. When the tone of the feedback was hostile, children of mothers who had been depressed during the children’s lifetimes were significantly more likely to make internal attributions for mistakes than children of nondepressed mothers. In addition, among children with low temperamental negative affectivity, in the presence of negative tone, negative content significantly predicted more internal attributions for the errors. Findings are discussed in terms of understanding the role of evaluative feedback in children’s emerging social cognitions and affect.

Background: Thought records are a core component of Cognitive Behavior Therapy. Over time, thought records have been modified to suit various needs or preferences. A diversity of thought records have been developed, which include differing components and cognitive change strategies. Yet, due to a lack of specificity in the literature and field, different thought records are often treated as though they are interchangeable. Limited extant literature suggests that differing thought records may have unique clinical effects. However, meta-analyzing the comparable or differing effects of the distinct extant thought records is impeded by the lack of a coding system for thought records. Objective: The current study sought to prepare a way for further understanding the differential utility and effectiveness of different iterations of thought records by creating a coding system, which is described in detail. This coding system will be used to guide future research into which thought records work best for which problems. Method: Thought records were gathered from seminal texts and solicited from the certified members of the Academy of Cognitive Therapy and the American Board of Behavioral and Cognitive Psychology. Results: In total, 110 non-identical thought records were gathered and coded into 55 unique combinations. These results demonstrate that the variability of thought records used by qualified therapists extends well beyond those found in seminal CBT texts. Conclusion: This broad diversity justifies the need for a coding system to inform future lines of research.

Although some treatments for depression in children and adolescents have been found to be efficacious, the effects sizes have tended to be modest. Thus, there is considerable room to improve upon existing depression treatments. Some children may respond poorly because they do not yet have the cognitive, social, or emotional maturity needed to understand and apply the skills being taught in therapy. Therefore, treatments for depression may need to be tailored to match children's ability to both comprehend and implement the therapeutic techniques. This review outlines the steps needed for such developmental tailoring: (a) Specify the skills being taught in depression treatments; (b) identify what cognitive, social, and emotional developmental abilities are needed to attain these skills; (c) describe the normative developmental course of these skills and how to determine a child's developmental level; and (d) use this information to design an individualized treatment plan. Possible approaches to intervening include: alter the therapy to meet the child's level of development, train the child on the skills needed to engage in the therapy, or apply a dynamic assessment approach that integrates evaluation into treatment and measures children's current abilities as well as their potential.

Use of expert-led workshops plus consultation has been established as an effective strategy for training community mental health (CMH) clinicians in evidence-based practices (EBPs). Because of high rates of staff turnover, this strategy inadequately addresses the need to maintain capacity to deliver EBPs. This study examined knowledge, competency, and retention outcomes of a two-phase model developed to build capacity for an EBP in CMH programs.In the first phase, an initial training cohort in each CMH program participated in in-person workshops followed by expert-led consultation (in-person, expert-led [IPEL] phase) (N=214 clinicians). After this cohort completed training, new staff members participated in Web-based training (in place of in-person workshops), followed by peer-led consultation with the initial cohort (Web-based, trained-peer [WBTP] phase) (N=148). Tests of noninferiority assessed whether WBTP was not inferior to IPEL at increasing clinician cognitive-behavioral therapy (CBT) competency, as measured by the Cognitive Therapy Rating Scale.WBTP was not inferior to IPEL at developing clinician competency. Hierarchical linear models showed no significant differences in CBT knowledge acquisition between the two phases. Survival analyses indicated that WBTP trainees were less likely than IPEL trainees to complete training. In terms of time required from experts, WBTP required 8% of the resources of IPEL.After an initial investment to build in-house CBT expertise, CMH programs were able to use a WBTP model to broaden their own capacity for high-fidelity CBT. IPEL followed by WBTP offers an effective alternative to build EBP capacity in CMH programs, rather than reliance on external experts.

OBJECTIVE Progress bringing evidence-based practice (EBP) to community behavioral health (CBH) has been slow. This study investigated feasibility, acceptability, and fidelity outcomes of a program to implement transdiagnostic cognitive therapy (CT) across diverse CBH settings, in response to a policy shift toward EBP. METHOD Clinicians (n = 348) from 30 CBH programs participated in workshops and 6 months of consultation. Clinician retention was examined to assess feasibility, and clinician feedback and attitudes were evaluated to assess implementation acceptability. Experts rated clinicians' work samples at baseline, mid-, and end-of-consultation with the Cognitive Therapy Rating Scale (CTRS) to assess fidelity. RESULTS Feasibility was demonstrated through high program retention (i.e., only 4.9% of clinicians withdrew). Turnover of clinicians who participated was low (13.5%) compared to typical CBH turnover rates, even during the high-demand training period. Clinicians reported high acceptability of EBP and CT, and self-reported comfort using CT improved significantly over time. Most clinicians (79.6%) reached established benchmarks of CT competency by the final assessment point. Mixed-effects hierarchical linear models indicated that CTRS scores increased significantly from baseline to the competency assessment (p < .001), on average by 18.65 points. Outcomes did not vary significantly between settings (i.e., outpatient vs. other). CONCLUSIONS Even clinicians motivated by policy-change rather than self-nomination may feasibly be trained to deliver a case-conceptualization driven EBP with high levels of competency and acceptability. (PsycINFO Database Record

The present prospective study examined the relations among stressful life events, coping, and depressive symptoms in children at varied risk for depression. Participants were 227 children between 7 and 17 years old (mean age = 12.13 years, SD = 2.31, 54.6 % female) who were part of a longitudinal study of depressed and nondepressed parents and their children. Youth completed measures assessing stressful life events and coping strategies at four time points over 22 months. Children's depressive symptoms were assessed at each time point by clinical interviews of parents and children, and children's self-report. Structural equation modeling indicated that stressful life events significantly predicted subsequent depressive symptoms. Bootstrap analyses of the indirect effects in three different models revealed that primary control engagement coping and disengagement coping strategies partially mediated the relation between stressful life events and children's depressive symptoms across time. Regarding the direction of effects, more consistent relations were found for coping as a mediator of the link from stress to depressive symptoms than from symptoms to stress. Thus, one potential mechanism by which stressful life events may contribute to depressive symptoms in children is through less use of primary control coping and greater use of disengagement coping strategies. This is consistent with the view that the adverse effects of stress may contribute to impairments in the ability to cope effectively.

HIV-1 CRF.AE-01 (formerly subtype E) infection is highly prevalent in Southeast Asia. Despite success with public health measures, the development of an effective CRF01.AE vaccine is critical to the control of this epidemic. Sera from the open-label arms of the first clinical trial of a bivalent HIV gp120 SF2/CM235 (subtypes B and CRF.AE-01, respectively) vaccine were evaluated for the presence of gp120-specific binding (BAb) and neutralizing antibody (NAb). Twelve pre- and postvaccination sera pairs were tested for CM235 BAb; anti-gp120 CM235 BAb was found in all postvaccination samples. The 12 pre- and postvaccination (1 month after third vaccination) serum pairs were evaluated in several neutralization formats: heterologous T cell line adapted (TCLA) NP03/H9, homologous CM235/PBMC, CM235/dendritic cell, and CM235M4-C4.6/A3R5. A3R5 is a CCR5+ T cell line, and CM235M4-C4.6 is the homologous CM235 virus adapted to growth in A3R5 cells. All volunteers developed BAb, but meaningful NAb was not demonstrable against primary isolate CM235. Using the TCLA CRF01.AE virus NP03 in H9 cells, 9 of 12 persons had NAb with a geometric mean titer (GMT) of 46. The CM235M4-C4.6 virus in A3R5 cells also detected NAb in 9 of 12 persons, with a GMT of 41. CM235M4-C4.6/A3R5 detected NAb in two persons with negligible NAb to NP03/H9 and vice versa. Whether the NAb detected by the CM235M4-C4.6/A3R5 system is qualitatively different from those in more traditional NP03/H9 assays will require further study.

Preclinical data are reported that support a human immunodeficiency virus (HIV) vaccine strategy using recombinant canarypox-HIV vectors (ALVAC-HIV) to load human dendritic cells (DCs) with HIV antigens. Clinical-grade DCs were infected with good manufacturing practice-grade ALVAC-HIV vaccine constructs. ALVAC infection, HIV gene expression, and DC viability and function were monitored by use of immunohistochemistry, flow cytometry, blastogenesis assays, antigen-specific interferon (IFN)-gamma enzyme-linked immunospot assay, and enzyme-linked immunosorbent assay protein detection. The vaccines infected both immature and mature DCs, and intracellular HIV-1 Gag protein was detected within hours. ALVAC-HIV induced DC maturation that was mediated by tumor necrosis factor-alpha and induced DC apoptosis that was directly related to the length of vaccine exposure. Of importance, the infected DCs remained functional in T cell stimulation assays and induced HIV antigen-specific CD8(+) T cell production of IFN-gamma from cells of HIV-1-infected individuals. These data support an ongoing HIV vaccine trial comparing conventional vaccine delivery routes with ex vivo vaccine-loaded autologous DCs for immunogenicity in HIV-1-uninfected volunteers.

In Thailand, the predominant HIV subtype is E, rather than Subtype B as in North America and Europe, and the predominant mode of transmission is heterosexual contact. Subtype E has the ability to replicate in vitro in Langerhans cells. We hypothesized that this cell type might constitute a reservoir for the HIV virus in vaginal mucosa of asymptomatic carriers. To examine this hypothesis, we compared vaginal tissue histology in HIV-1-seropositive cases with seronegative cases and determined the immunophenotype of HIV-1-infected cells, their numbers, and their distribution in vaginal mucosa. Vaginal biopsies were performed at four different sites from six asymptomatic HIV-1 Subtype E-infected persons and from six seronegative cases at necropsy and examined histologically. Immunophenotyping was performed using immunoperoxidase for Gag p24 HIV, CD3, CD20, CD68, CD1a, S-100 and p55 antigens and by double labeling, combining immunoperoxidase with alkaline phosphatase using pairs of the above antigens. Twenty of twenty-four vaginal biopsies (83.3%) from HIV-seropositive cases showed definite inflammation compared to five of twenty-four vaginal necropsies (20.8%) from HIV-seronegative cases. One third of HIV-seropositive biopsies (8/24) demonstrated p24-positive cells in the epithelium, whereas three-fourths (18/24) of the biopsies revealed p24-positive cells in the lamina propria. All seropositive patients showed positive cells in at least one biopsy, but not all biopsies contained positive cells. Infected cells were more frequently observed at sites of greater inflammation. The dendritic cell count in HIV-seropositive vaginal epithelium was significantly higher than that observed in the seronegative cases (P =.004). The majority of p24-positive cells in the vaginal epithelium were Langerhans cells (CD1a+/S-100+), whereas in the lamina propria, about half of p24-positive cells were Langerhans-related dendritic cells (p55+ and S-100+) and half were T lymphocytes. In conclusion, the increased propensity for heterosexual transmission of Subtype E may be related to vaginal inflammation, leading to the accumulation of Langerhans cells and related dendritic cells which, once infected with HIV, can act as a reservoir for further virus transmission.

Recombinant avipox viruses are being widely evaluated as vaccines. To address how these viruses, which replicate poorly in mammalian cells, might be immunogenic, we studied how canarypox virus (ALVAC) interacts with primate antigen-presenting dendritic cells (DCs). When human and rhesus macaque monocyte-derived DCs were exposed to recombinant ALVAC, immature DCs were most susceptible to infection. However, many of the infected cells underwent apoptotic cell death, and dying infected cells were engulfed by uninfected DCs. Furthermore, a subset of DCs matured in the ALVAC-exposed DC cultures. DC maturation coincided with tumor necrosis factor alpha (TNF-α) secretion and was significantly blocked in the presence of anti-TNF-α antibodies. Interestingly, inhibition of apoptosis with a caspase 3 inhibitor also reduced some of the maturation induced by exposure to ALVAC. This indicates that both TNF-α and the presence of primarily apoptotic cells contributed to DC maturation. Therefore, infection of immature primate DCs with ALVAC results in apoptotic death of infected cells, which can be internalized by noninfected DCs driving DC maturation in the presence of the TNF-α secreted concomitantly by exposed cells. This suggests an important mechanism that may influence the immunogenicity of avipox virus vectors.

To pursue the capacity of monkey dendritic cells (DC) to be modified by adenoviral vectors and present the encoded antigens, we generated DC from blood monocytes and infected them with recombinant adenoviruses encoding GFP reporter and SIVgag or nef genes. Recombinant, E1- and E3-deleted, adenoviruses could transfect immature DC to >90% efficiency. When differentiated in the presence of a maturation stimulus, the infected cells were identical to control uninfected DC in surface markers and potent stimulatory activity for the mixed leukocyte reaction. Recombinant adeno-SIVgag was comparable to vaccinia-gag in stimulating IFN-gamma-secreting CD8(+) T cells from PBMC of macaques vaccinated with SIV(mac239) Deltanef and challenged with pathogenic SIV or chimeric SIV/HIV. Small numbers of adeno-SIVgag-infected DC were sufficient to trigger specific ELISPOT responses by CD8(+) T cells from these animals. Some CD4(+) IFN-gamma-secreting cells were also found in the three of eight vaccinated animals with the highest CD8(+) responses. T cells from control animals did not respond to DC transfected with adeno-gag. Therefore recombinant adenoviruses efficiently transfect monkey DC in a nonperturbing fashion, and these DC efficiently present antigens to SIVgag immune CD8(+) T cells. These findings will allow autologous DC, expressing SIV genes with high efficiency, to be tested in vivo to achieve strong specific T cell immunity.

Human immunodeficiency virus-1 (HIV-1) infection is a fatal retroviral infection that may first present clinically as enlargement of the lymphoid tissues of Waldeyer's ring. These tissues are a major site of viral replication. The presence of the virus in these tissues causes a unique constellation of diagnostic histopathologic features, including florid follicular hyperplasia, follicle lysis, and productively HIV-1-infected multinucleated giant cells of probable dendritic cell origin. Serologic evaluation is confirmatory of HIV infection. With the recent advances in antiretroviral chemotherapy, the early institution of which may significantly prolong life and disease-free interval, the recognition of the clinical and pathologic parameters of HIV-related enlargement of Waldeyer's ring tissues is essential.

Human immunodeficiency virus-type 1 (HIV-1) replicates actively in infected individuals, yet cells with intracellular depots of viral protein are observed only infrequently. Many cells expressing the HIV-1 Gag protein were detected at the surface of the nasopharyngeal tonsil or adenoid. This infected mucosal surface contained T cells and dendritic cells, two cell types that together support HIV-1 replication in culture. The infected cells were multinucleated syncytia and expressed the S100 and p55 dendritic cell markers. Eleven of the 13 specimens analyzed were from donors who did not have symptoms of acquired immunodeficiency syndrome (AIDS). The interaction of dendritic cells and T cells in mucosa may support HIV-1 replication, even in subclinical stages of infection.

HIV-1 infection of tonsils takes place when virus spreads systemically, and may occur when tonsillar tissue serves as the initial portal of HIV-1 entry. The HIV replication cycle includes the production of regulatory and accessory gene mRNAs, produced by splicing of genomic mRNA, that are hallmarks of de novo virus production. We sought to demonstrate, for the first time, the presence of multiply spliced viral RNA transcripts in archival tissue as a marker for active virus replication. Further, amplified cDNA sequences from unspliced pol gene mRNA were used to define the genetic subtype of HIV-1 within these tissues. RNA was extracted from surgical pathological, formalin-fixed, paraffin-embedded specimens, and RT-PCR was performed with primers for unspliced and multiply spliced HIV-1 transcripts. Amplification products were analyzed by agarose gel electrophoresis and their specificity was confirmed by sequencing and Southern blot hybridization. Unspliced HIV-1 pol transcripts yielded cDNA amplicons of 184 base pairs (bp) that were cloned and sequenced. Phylogenetic analysis revealed these sequences to be of HIV-1 subtype B. Multiply spliced transcripts specific for the tat/rev (173 bp), tat (268 bp), and tat/rev/nef (146 bp) regulatory gene mRNAs could be demonstrated in all cases. These results support the demonstration of active replication of HIV-1 in archival tonsillar tissues previously shown by p24 antigen staining. They also show the feasibility of performing molecular epidemiologic studies on HIV-1 cDNA sequences from archived pathologic specimens.

Dengue virus infections are an emerging global threat. Severe dengue infection is manifested as dengue hemorrhagic fever and dengue shock syndrome, both of which can be fatal complications. Factors predisposing to complicated disease and pathogenesis of severe infections are discussed. Using immunohistochemistry, immunofluorescence, flow cytometry, and ELISA techniques, we studied the cellular targets of dengue virus infection, at both the clinical (in vivo) and the laboratory (in vitro) level. Resident skin dendritic cells are targets of dengue virus infection as demonstrated in a skin biopsy from a dengue vaccine recipient. We show that factors influencing infection of monocytes/macrophages and dendritic cells are different. Immature dendritic cells were found to be the cells most permissive for dengue infection and maybe early targets for infection. Immature dendritic cells exposed to dengue virus produce TNF-alpha protein. Some of these immature dendritic cells undergo TNF-alpha mediated maturation as a consequence of exposure to the dengue virus.

Thai residents have a greater risk of heterosexual transmission of human immunodeficiency virus (HIV) than do US residents. To analyze host factors associated with heterosexual transmission, vaginal epithelial biopsies from HIV-seropositive Thai and US women were evaluated for tissue virus load and histologic makeup. In all, 84% of Thai and 14% of US women exhibited a chronic inflammatory T cell infiltrate in the vaginal epithelium. In Thai tissue, the infiltrate was associated with elevated levels of HIV RNA in the epidermis. Uninfected Thai women also had vaginal epithelial inflammation. Inflammation did not correlate with sexually transmitted diseases or HIV disease stage. The higher rates and increased risk of heterosexual transmission in Thailand may be due to chronic inflammation at the site where the virus is transmitted, which leads to the accumulation of activated T cells. Such cells might act as targets for initial viral infection and subsequently as reservoirs that support efficient transmission.

Transcutaneous immunization, a topical vaccine application, combines the advantages of needle-free delivery while targeting the immunologically rich milieu of the skin. In animal studies, this simple technique induces robust systemic and mucosal antibodies against vaccine antigens. Here, we demonstrate safe application of a patch containing heat-labile enterotoxin (LT, derived from Escherichia coli) to humans, resulting in robust LT-antibody responses. These findings indicate that TCI is feasible for human immunization, and suggest that TCI may enhance efficacy as well as improve vaccine delivery.

Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukocyte antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.

The role of antibody in protection against human immunodeficiency virus (HIV-1) has been difficult to study in animal models because most primary HIV-1 strains do not infect nonhuman primates. Using a chimeric simian/human immunodeficiency virus (SHIV) based on the envelope of a primary isolate (HIV-89.6), we performed passive-transfer experiments in rhesus macaques to study the role of anti-envelope antibodies in protection. Based on prior in vitro data showing neutralization synergy by antibody combinations, we evaluated HIV immune globulin (HIVIG), and human monoclonal antibodies (MAbs) 2F5 and 2G12 given alone, compared with the double combination 2F5/2G12 and the triple combination HIVIG/2F5/2G12. Antibodies were administered 24 h prior to intravenous challenge with the pathogenic SHIV-89.6PD. Six control monkeys displayed high plasma viremia, rapid CD4 + -cell decline, and clinical AIDS within 14 weeks. Of six animals given HIVIG/2F5/2G12, three were completely protected; the remaining three animals became SHIV infected but displayed reduced plasma viremia and near normal CD4 + -cell counts. One of three monkeys given 2F5/2G12 exhibited only transient evidence of infection; the other two had marked reductions in viral load. All monkeys that received HIVIG, 2F5, or 2G12 alone became infected and developed high-level plasma viremia. However, compared to controls, monkeys that received HIVIG or MAb 2G12 displayed a less profound drop in CD4 + T cells and a more benign clinical course. These data indicate a general correlation between in vitro neutralization and protection and suggest that a vaccine that elicits neutralizing antibody should have a protective effect against HIV-1 infection or disease.

Prevention of the initial infection of mucosal dendritic cells (DC) and interruption of the subsequent transmission of HIV-1 from DC to T cells are likely to be important attributes of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. While anti-HIV-1 neutralizing antibodies have been difficult to elicit by immunization, there are several human monoclonal antibodies (MAbs) that effectively neutralize virus infection of activated T cells. We investigated the ability of three well-characterized neutralizing MAbs (IgG1b12, 2F5, and 2G12) to block HIV-1 infection of human DC. DC were generated from CD14 + blood cells or obtained from cadaveric human skin. The MAbs prevented viral entry into purified DC and the ensuing productive infection in DC/T-cell cultures. When DC were first pulsed with HIV-1, MAbs blocked the subsequent transmission to unstimulated CD3 + T cells. Thus, neutralizing antibodies can block HIV-1 infection of DC and the cell-to-cell transmission of virus from infected DC to T cells. These data suggest that neutralizing antibodies could interrupt the initial events associated with mucosal transmission and regional spread of HIV-1.

A patient is described who rapidly progressed from primary human immunodeficiency virus (HIV) type 1 infection to death without seroconversion but with consistently high plasma viremia. His asymptomatic sex partner had been HIV-1 seropositive for >8 years prior to transmission. Analysis of viral sequences from these subjects and controls confirmed the transmission event. Although the biologic properties of the patient's virus were unremarkable, he had poor functional immune responses to HIV and an HLA haplotype associated with rapid disease progression. The disparity between immune responses and clinical course in this transmission pair, coupled with infection with an unremarkable HIV-1 isolate, underscores the crucial importance of host factors in HIV-1 pathogenesis.

We report 12 cases in which the histomorphologic changes of the nasopharyngeal tonsils (adenoids) or palatine tonsils suggest infection with the human immunodeficiency virus (HIV). The patients included 10 men and two women, aged 20 to 42 years (median, 33 years). The clinical presentation included airway obstruction, pharyngitis, fever, and a tonsillar or adenoidal mass lesion. Histologic evaluation of the excised adenoids or tonsils in 10 of the cases demonstrated a spectrum of changes including florid follicular hyperplasia, follicle lysis, attenuated mantle zone, and the presence of multinucleated giant cells (MGC). The latter characteristically localized adjacent to the surface or tonsillar crypt epithelium. Two of the 12 cases showed marked lymphoid depletion with absent germinal centers, plasmacytosis, and stromal vascular proliferation. Immunohistochemical evaluation for HIV p24 core protein showed reactivity in 10 of 12 cases localized to follicular dendritic cell network (FDC), the MGC, scattered interfollicular lymphoid cells, and cells identified within the surface or crypt epithelium. Localization of viral RNA by in situ hybridization paralleled the HIV p24 immunohistochemical findings. Additional significant findings included the presence of both CD-68 and S-100 protein in the MGC and the presence of S-100 protein in dendritic cells. Other than HIV, no microorganisms were identified. At the time of presentation, eight patients were not known to be a risk for HIV infection, nor were they known to be HIV infected or suffering from AIDS. In these patients, HIV infection was suspected on the basis of the histologic changes seen in the resected tonsillar and adenoidal tissue. Serologic evaluation (by enzyme-linked immunosorbent assay), confirmed the presence of HIV infection. Our findings suggest the possibility of HIV dissemination through the upper aero-digestive tract mucosa via target cells, such as intraepithelial dendritic cells, submucosal macrophages, and T-lymphocytes. Subsequent presentation of viral antigens to the tonsillar and adenoidal lymphoid tissues results in enlargement of these structures that clinically may simulate a neoplastic proliferation but causes histomorphologic changes that are highly suspicious for HIV infection even in asymptomatic HIV-positive patients.

The development of the human immunodeficiency virus-1 (HIV-1)/simian immunodeficiency virus (SIV) chimeric virus macaque model (SHIV) permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, others, and we have shown that passively infused antibody can protect against an intravenous challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. After controlling the macaque estrous cycle with progesterone, anti-HIV-1 neutralizing monoclonal antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all five control monkeys displayed high plasma viremia and rapid CD4 cell decline, 14 antibody-treated macaques were either completely protected against infection or against pathogenic manifestations of SHIV-infection. Infusion of all three antibodies together provided the greatest amount of protection, but a single monoclonal antibody, with modest virus neutralizing activity, was also protective. Compared with our previous intravenous challenge study with the same virus and antibodies, the data indicated that greater protection was achieved after vaginal challenge. This study demonstrates that antibodies can affect transmission and subsequent disease course after vaginal SHIV-challenge; the data begin to define the type of antibody response that could play a role in protection against mucosal transmission of HIV-1.

We have evaluated the in vivo distribution of the major human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) coreceptors, CXCR4, CCR3, and CCR5, in both rhesus macaques and humans. T lymphocytes and macrophages in both lymphoid and nonlymphoid tissues are the major cell populations expressing HIV/SIV coreceptors, reaffirming that these cells are the major targets of HIV/SIV infection in vivo. In lymphoid tissues such as the lymph node and the thymus, approximately 1 to 10% of the T lymphocytes and macrophages are coreceptor positive. However, coreceptor expression was not detected on follicular dendritic cells (FDC) in lymph nodes, suggesting that the ability of FDC to trap extracellular virions is unlikely to be mediated by a coreceptor-specific mechanism. In the thymus, a large number of immature and mature T lymphocytes express CXCR4, which may render these cells susceptible to infection by syncytium-inducing viral variants that use this coreceptor for entry. In addition, various degrees of coreceptor expression are found among different tissues and also among different cells within the same tissues. Coreceptor-positive cells are more frequently identified in the colon than in the rectum and more frequently identified in the cervix than in the vagina, suggesting that the expression levels of coreceptors are differentially regulated at different anatomic sites. Furthermore, extremely high levels of CXCR4 and CCR3 expression are found on the neurons from both the central and peripheral nervous systems. These findings may be helpful in understanding certain aspects of HIV and SIV pathogenesis and transmission.