Biomedical subjects

Steven D Douglas

Publications and source records attributed to Steven D Douglas.

At least 55 records · Page 3Linked to original sources

PubMed2003

Human neuronal cells (NT2-N) express functional substance P and neurokinin-1 receptor coupled to MIP-1 beta expression.

Substance P (SP), the most extensively studied and potent member of the tachykinin family, is a major modulator of inflammation and immunomodulatory activities within the central and peripheral nervous systems. We have examined the gene expression of SP and its receptor in a human neuronal cell line (NT2-N). Using reverse transcribed polymerase chain reaction (RT-PCR), the four isoforms of preprotachykinin-A gene transcripts (alpha, beta, gamma, and delta) were detected in the NT2-N. We also identified the presence of mRNA for neurokinin-1 receptor (NK-1R), a primary receptor for SP, in the NT2-N cells. Concomitant with NT2 cell differentiation into neurons, SP and NK-1R mRNA expression increased consistently. Intracellular SP and cell membrane NK-1R immunoreactivity were all observed in NT2-N cells. Most importantly, we demonstrated that SP and NK-1R presented in NT2-N cells are functionally involved in the regulation of macrophage inflammatory protein 1 beta (MIP-1beta), an important beta-chemokine participating in the activation and directional migration of immune cells to sites of central nervous systems (CNS) inflammation. Thus, SP and its receptor may play an important role in modulation of neuronal functions related to regulation of immune activities within the CNS. The NT2-N cell line is well suited for in vitro investigations of the SP-NK-1R pathway in immune responses and inflammation in the CNS.

Cells, Cultured↗

PubMed2003

The effects of avoidance on cytotoxic/suppressor T cells in women with cervical lesions.

The purpose of this study was to examine the relationship between avoidant and intrusive ideation about cancer risk and immune responses among women with mild cervical dysplasia. Participants were 54 women undergoing diagnostic follow-up (i.e. colposcopy) for an abnormal Pap smear test result. Baseline assessments, collected prior to the colposcopy appointment, included demographic and medical history, levels of depression, and the intrusion and avoidance subscales of the Revised Impact of Events Scale. In addition, a sample of blood was obtained at baseline and 6-month follow-up for immune assessments. Hierarchical regression analyses revealed that higher levels of cognitive and behavioral avoidance at baseline predicted a significantly lower percentage of circulating cytotoxic/suppressor T cells (CD3(+)/CD8(+)) at 6-month follow-up, after controlling for baseline levels of cytotoxic/suppressor T cells and potential confounding variables (e.g. age, smoking status). Baseline intrusive ideation was unrelated to changes in percentage of cytotoxic/suppressor T cells. Avoidant ideation, but not intrusive ideation or depression, appears to be associated with alterations in immunologic measures in women with cervical lesions. The findings suggest that it may be important to evaluate the impact of cognitive and behavioral avoidance on progression of precancerous cervical lesions.

Adolescent↗

PubMed2003

Association of depression, CD8+ T lymphocytes, and natural killer cell activity: implications for morbidity and mortality in Human immunodeficiency virus disease.

A heightened risk of mood disorders, such as major depression, and acute depressive symptoms has been observed among HIV-seropositive individuals since the start of the AIDS epidemic, and an accumulating body of data now shows that depression may have an impact on morbidity and mortality among individuals with HIV disease. Although the specific physiologic mechanisms involved in this process have not been delineated, there is some evidence to suggest that certain components of innate immunity, including killer lymphocytes such as CD8+ T lymphocytes and natural killer cells, may represent key pathways through which depression affects HIV disease progression. This paper reviews some of the main studies examining the effects of depression on immunity and HIV disease progression and discusses the potential role of killer lymphocytes as an underlying mechanism by which depression may impact morbidity and mortality.

CD8-Positive T-Lymphocytes↗

PubMed2003

Interleukin-1beta induces macrophage inflammatory protein-1beta expression in human hepatocytes.

The investigation of factors that regulate expression of CC-chemokines, the important mediators in immune responses and inflammation processes, has an important significance in understanding the immunopathogenesis of liver diseases. We examined the role of interleukin-1beta (IL-1beta), a multifunctional cytokine, in regulating the expression of macrophage inflammatory protein (MIP)-1beta in human hepatocytes (Huh7 and HepG2). IL-1beta significantly enhanced MIP-1beta expression in these cells at both the mRNA and protein levels. Cytokine-enriched supernatants from monocyte-derived macrophage (MDM) cultures also induced MIP-1beta expression. IL-1beta is responsible for MDM supernatant-mediated up-regulation of MIP-1beta since the antibody to IL-1beta abolished MDM supernatant action. Investigation of the mechanism involved in MIP-1beta induction by IL-1beta showed that IL-1beta activated the nuclear factor kappa B (NF-kappaB) promoter in Huh7 cells. In addition, caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, not only abolished IL-1beta-mediated NF-kappaB promoter activation, but also blocked IL-1beta-induced MIP-1beta expression. These observations suggest that IL-1beta-mediated up-regulation of MIP-1beta production in the hepatic cells may contribute a critical mechanism for continuous recruitment of inflammatory cell to liver and maintenance of inflammation.

Caffeic Acids↗

PubMed2003

Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.

BACKGROUND: Peripheral blood lymphocyte subsets need to be determined in a large, urban, minority-predominant cohort of healthy children to serve as suitable control subjects for the interpretation of the appearance of these cells in several disease conditions, notably pediatric HIV-1 infection. OBJECTIVE: We sought to determine the distribution of lymphocyte subsets in healthy urban-dwelling infants, children, and adolescents in the United States. METHODS: Lymphocyte subsets were determined by means of 3-color flow cytometry in a cross-sectional study of 807 HIV-unexposed children from birth through 18 years of age. RESULTS: Cell-surface marker analysis demonstrated that age was an extremely important variable in 24 lymphocyte subset distributions measured as percentages or absolute counts--eg, the CD4 (helper) T cell, CD8 (cytotoxic) T cell, CD19 B cell, CD4CD45RACD62L (naive helper) T cell, CD3CD4CD45RO (memory helper) T cell, CD8HLA-DRCD38 (activated cytotoxic) T cell, and CD8CD28 (activation primed cytotoxic) T cell. The testing laboratory proved to be an important variable, indicating the need for using the same laboratory or group of laboratories to assay an individual's blood over time and to assay control and ill or treated populations. Sex and race-ethnicity were much less important. CONCLUSION: The results of this study provide a control population for assessment of the effects of HIV infection on the normal development and distribution of lymphocyte subsets in children of both sexes, all races, and all ethnic backgrounds from birth through 18 years of age in an urban population. This study's findings will also prove invaluable in interpreting the immune changes in children with many other chronic diseases, such as primary immunodeficiency, malignancy, rheumatoid arthritis, and asthma.

Adolescent↗

PubMed2003

Morphine enhances hepatitis C virus (HCV) replicon expression.

Little information is available regarding whether substance abuse enhances hepatitis C virus (HCV) replication and promotes HCV disease progression. We investigated whether morphine alters HCV mRNA expression in HCV replicon-containing liver cells. Morphine significantly increased HCV mRNA expression, an effect which could be abolished by either of the opioid receptor antagonists, naltrexone or beta-funaltrexamine. Investigation of the mechanism responsible for this enhancement of HCV replicon expression demonstrated that morphine activated NF-kappaB promoter and that caffeic acid phenethyl ester, a specific inhibitor of the activation of NF-kappaB, blocked morphine-activated HCV RNA expression. In addition, morphine compromised the anti-HCV effect of interferon alpha (IFN-alpha). Our in vitro data indicate that morphine may play an important role as a positive regulator of HCV replication in human hepatic cells and may compromise IFN-alpha therapy.

Antiviral Agents↗

PubMed2003

Depression and HIV infection: impact on immune function and disease progression.

Can psychological factors, such as depression, affect human immunodeficiency virus progression? HIV infection is viewed as a chronic illness in which those infected often confront a number of emotional challenges and physical health and disease-related issues. Over the past 20 years, there has been increasing evidence that depression and other mood-related disturbances are commonly observed among HIV-positive individuals. There is also mounting data showing that depressive symptoms might further impact upon specific elements of immune system functioning and influence quality of life and health status. This paper will highlight studies examining the prevalence of depression during HIV infection and review some of the evidence examining the impact of depressive symptoms on immune function and HIV disease progression.

CD4 Lymphocyte Count↗

PubMed2003

Neuropsychopharmacologic treatment of depression and other neuropsychiatric disorders in HIV-infected individuals.

How can neuropsychiatric disorders and syndromes be underdiagnosed and inadequately treated in individuals infected with human immunodeficiency virus? Depression in particular is among the most prevalent diagnoses and there is a solid foundation of data from controlled clinical studies that has begun to examine the efficacy of various antidepressants in HIV-infected persons. This article summarizes essential findings pertaining to the use of psychotropic medications to treat depression and other neuropsychiatric disorders in the context of immunodeficiency. This includes discussion of clinically significant treatment considerations (eg, efficacy, side effects, drug-drug interactions) derived from the existing literature. Taken together, there is compelling evidence that psychopharmacologic intervention can improve the quality of life of mentally ill HIV-infected individuals.

AIDS Dementia Complex↗

PubMed2003

Interleukin-1beta stimulates macrophage inflammatory protein-1alpha and -1beta expression in human neuronal cells (NT2-N).

Chemokines are important mediators in immune responses and inflammatory processes of neuroimmunologic and infectious diseases. Although chemokines are expressed predominantly by cells of the immune system, neurons also express chemokines and chemokine receptors. We report herein that human neuronal cells (NT2-N) produce macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha and MIP-1beta), which could be enhanced by interleukin (IL)-1beta at both mRNA and protein levels. The addition of supernatants from human peripheral blood monocyte-derived macrophage (MDM) cultures induced MIP-1beta mRNA expression in NT2-N cells. Anti-IL-1beta antibody removed most, but not all, of the MDM culture supernatant-induced MIP-1beta mRNA expression in NT2-N cells, suggesting that IL-1beta in the MDM culture supernatants is a major factor in the induction of MIP-1beta expression. Investigation of the mechanism(s) responsible for IL-1beta-induced MIP-1alpha and -1beta expression demonstrated that IL-1beta activated nuclear factor kappa B (NF-kappaB) promoter-directed luciferase activity in NT2-N cells. Caffeic acid phenethyl ester, a potent and specific inhibitor of activation of NF-kappaB, not only blocked IL-1beta-induced activation of the NF-kappaB promoter but also decreased IL-1beta-induced MIP-1alpha and -1beta expression in NT2-N cells. These data suggest that NF-kappaB is at least partially involved in the IL-1beta-mediated action on MIP-1alpha and -1beta in NT2-N cells. IL-1beta-mediated up-regulation of beta-chemokine expression may have important implications in the immunopathogenesis of inflammatory diseases in the CNS.

Cell Line↗

PubMed2003

Alcohol potentiates hepatitis C virus replicon expression.

Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (HCV) effect of interferon alfa (IFN-alpha) in patients with HCV infection. It is unknown, however, whether alcohol enhances HCV replication and promotes HCV disease progression. The availability of the HCV replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and HCV replicon expression. We determined whether alcohol enhances HCV RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-alpha. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor kappaB (NF-kappaB) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression. In conclusion, alcohol, probably through the activation of NF-kappaB and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-alpha. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-alpha-based therapy against HCV infection.

Antidotes↗

PubMed2003

The relationships between substance abuse, psychosocial variables, and natural killer cell enumeration and function in HIV-infected and high-risk uninfected adolescents.

UNLABELLED: This report examines the relationship between substance use, psychosocial stressors, and natural killer (NK) cell enumeration and function in HIV-infected and high-risk uninfected adolescents. We studied the association of demographic characteristics; self-report measures of alcohol, tobacco, and marijuana use; and self-report measures of psychosocial stressors (depressive symptoms, anxiety) with three immune outcomes: NK (CD3(-)CD16(+)CD56(+)) absolute counts, lytic units per peripheral blood mononuclear cells (PBMCs), and lytic units per NK cell. In addition, we determined the association of HIV disease stage, antiretroviral therapy (ART), CD4(+) T-cell count, and viral load with these outcomes in the subset of HIV-infected adolescents. METHODS: This cross-sectional analysis reports on data collected during a longitudinal observational study of adolescents (the REACH Study). A cross-sectional analysis was performed with data from the first visit for each subject that met criteria for concurrent (within 3 days) assessment of NK number and function, substance use, and psychosocial data. The data set represented 501 subjects. Analyses were performed separately for the HIV-seropositive and seronegative adolescents. In the HIV-seronegative population, there were no significant predictors of NK cell count and only female gender was significantly associated with CD3(-)CD16(+)CD56(+) NK lytic units per PBMC. Analysis of the HIV-seronegative cohort also showed that black race was significantly associated with higher lytic units per NK cell. RESULTS: In HIV-seropositive adolescents, we observed an association of female gender with lower NK cell number and lytic units per PBMC, but not with lytic units per NK cells. Current use of one or two antiretroviral drugs was predictive of lower NK numbers. This drug effect was also noted in the functional assay per PBMC but not per NK cell. Increasing worry scores and no marijuana use over the past 3 months were associated with lower functional NK measures per PBMC in HIV-seropositive youth. Laboratory-confirmed recent marijuana use was highly predictive of increased lytic activity calculated per NK cell. These effects were not observed in similar analyses of data from HIV-seronegative adolescents. Depressive symptoms, assessed with an epidemiologic screening tool, were not found to be predictive of NK cell number or function in either the HIV-seronegative or the HIV-seropositive subset. These findings document associations between substance abuse, psychosocial variables, and NK numbers and function in adolescents.

Adolescent↗

PubMed2003

CD4+ and CD8+ T cell receptor repertoire perturbations with normal levels of T cell receptor excision circles in HIV-infected, therapy-naive adolescents.

Our objective was to determine whether treatment-naive HIV-infected adolescents manifest abnormalities in thymus function and peripheral T cell repertoire, and to assess relationships of these immunologic characteristics with each other, with plasma HIV virus load, and T cell surface markers. TCR Vbeta repertoire was determined by CDR3 length spectratyping in purified CD4(+) and CD8(+) T cells of high-risk, HIV-negative adolescents and of treatment-naive, HIV-infected adolescents. Thymus function was investigated by the simultaneous examination of T cell receptor excision circles (TRECs) in the CD4(+) and CD8(+) T cell subsets. HIV-infected adolescents exhibited significantly greater perturbations in their TCR Vbeta repertoire in comparison with HIV-negative subjects. Perturbations in the CD8(+) T cell compartment were more profound in comparison with CD4(+) T cells. The CD4(+) TCR Vbeta perturbations were negatively correlated with the total and phenotypically naive CD4(+) T cells, and with CD4(+) TRECs. CD8(+) TRECs, although not correlated with CD8(+) TCR Vbeta perturbations, showed negative correlation with memory and activated CD8(+) T cells. Interestingly, TRECs in CD4(+) and CD8(+) T cells were not significantly different between HIV-infected and uninfected adolescents. The TCR Vbeta repertoire in adolescents is profoundly perturbed even in early stages of HIV infection, when total CD4(+) cell counts in most subjects are within normal limits. The correlative analyses demonstrating negative association of CD4(+) cell TRECs with CD4(+) TCR Vbeta perturbations and of CD8(+) TRECs with CD8(+) cell activation markers provide evidence of the intense activation of the central and peripheral immune compartments in this study population.

Adolescent↗

PubMed2003

Assessment of thymic activity in human immunodeficiency virus-negative and -positive adolescents by real-time PCR quantitation of T-cell receptor rearrangement excision circles.

Circular DNA molecules known as T-cell receptor rearrangement excision circles (TREC) arise during T-cell development and are present in cells that have recently emigrated from the thymus. In cross-sectional studies, the number of peripheral blood lymphocytes bearing TREC decreases with age, consistent with an anatomically demonstrated loss of thymic epithelial tissue. TREC numbers increase following hematopoietic stem cell transplantation and during therapy for human immunodeficiency virus (HIV) infection. Quantitation of TREC has therefore been proposed as a parameter of thymic activity. In this study, we used real-time PCR to quantify TREC in peripheral blood samples obtained longitudinally from HIV-seronegative adolescents. TREC values in peripheral blood T cells were very stable throughout adolescence, once thought to be a time of rapid involution of the thymus. In addition, in a cross-sectional analysis, we examined TREC values in a cohort of HIV-positive adolescents and found evidence of ongoing thymopoiesis in perinatally infected individuals, despite lifelong infection. These data demonstrate the utility of TREC assessment in adolescents and that HIV infection does not uniformly result in accelerated thymic involution in childhood.

Adolescent↗

PubMed2003

TH1 and TH2 cytokine mRNA and protein levels in human immunodeficiency virus (HIV)-seropositive and HIV-seronegative youths.

The roles of cytokines in the progression of human immunodeficiency virus (HIV)-associated disease are controversial. The patterns of innate cytokine production have been postulated to shift from TH1- to TH2-type cytokines with the progression of HIV-associated disease. Although there have been studies of cytokines in children and adults, no data are available on cytokine production in healthy or HIV-infected adolescents. We analyzed and characterized cytokine mRNA and protein levels for gamma interferon, interleukin 2 (IL-2), IL-4, and tumor necrosis factor alpha and protein levels of IL-6 in both stimulated and unstimulated peripheral blood mononuclear cells obtained from a large longitudinal, observational cohort study of HIV-seropositive and -seronegative adolescents. We correlated cytokine results with viral load and CD4(+)-T-cell counts as critical markers of disease progression in HIV-infected adolescents. These data were used to examine hypotheses related to the TH1-to-TH2 cytokine shift in a sample of HIV-infected adolescents. Five hundred twenty subjects participating in the REACH (Reaching for Excellence in Adolescent Care and Health) Project of the Adolescent Medicine HIV/AIDS Research Network contributed blood samples. Samples selected for the cross-sectional data set analyzed had to meet selection criteria developed to minimize the potential confounding effects of acute intercurrent illnesses or infections, recent vaccination for hepatitis, and altered hormone status and to optimize congruence of cytokine measurements with assays of viral load and CD4(+)-T-cell counts. Group differences in the proportions of subjects with detectable levels of each cytokine marker were compared. In the subset of subjects with detectable cytokine values, differences in detected values were compared across subgroups defined by HIV serostatus and among HIV-seropositive subjects by three viral load classifications. The study sample was 65% HIV seropositive, 71% African-American, and 75% female with a mean age of 17.4 years. HIV-seropositive subjects were relatively healthy with mean and median CD4(+)-T-cell counts of 534 and 499 cells/mm(3), respectively. Only 8.1% of subjects had CD4(+)-T-cell counts below 200 cells/mm(3), and 25% had viral loads that were below the threshold of detection (<400 copies/ml). Detailed analyses of these data indicate that there were no differences in cytokines detected in HIV-seropositive and HIV-seronegative adolescents, and there was no apparent relationship between the cytokine measurements and the viral load or CD4(+)-T-cell categorization, the parameters selected as markers of HIV-associated disease status. These adolescents, including the HIV-seropositive subjects, were relatively healthy, and the HIV-infected subjects were at an early stage in the course of their HIV-associated disease. On the basis of our data, we conclude that, early in the course of HIV-associated disease in adolescents, there are no detectable shifts from TH1 to TH2 cytokine production.

Adolescent↗

PubMed2003

Quantification of CCR5 mRNA in human lymphocytes and macrophages by real-time reverse transcriptase PCR assay.

CCR5, a beta-chemokine receptor, plays an important role in human immunodeficiency virus (HIV) infection of human immune cells, as it is a primary coreceptor for HIV entry into macrophages. We have applied a newly developed real-time reverse transcriptase PCR (RT-PCR) assay for the quantification of CCR5 mRNA in human blood immune cells. The CCR5 real-time RT-PCR assay has a sensitivity of 100 mRNA copies, with a dynamic range of detection between 10(2) and 10(6) copies of the CCR5 mRNA transcripts per reaction. The assay is highly reproducible, with an intra-assay coefficient of variation of the threshold cycle of less than 2.07%. When used for quantification of CCR5 mRNA in human monocyte-derived macrophages (MDM) and peripheral blood lymphocytes (PBL), the assay has precision and reproducibility. MDM expressed higher levels of CCR5 mRNA than did PBL. Thus, this assay has the potential and a wide application for the investigation of the role of CCR5 in inflammatory diseases and viral infections, including HIV disease.

Blood Cells↗

PubMed2002

Host genetic profiles predict virological and immunological control of HIV-1 infection in adolescents.

OBJECTIVE: To evaluate the correlation between host genetic profiles and virological and immunological outcomes among HIV-1-seropositive participants from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. METHODS: HLA class I and chemokine coreceptor (CCR) alleles and haplotypes were resolved in 227 HIV-1-seropositive adolescents (ages 13-18 years; 75% females; 71% African-Americans) and 183 HIV-seronegative individuals, with quarterly follow-up visits between 1996 and 2000. Each HLA and CCR variant with consistent risk and protective effect on HIV-1 pathogenesis was assigned a score of -1 and +1, respectively. All individual markers and genetic scores were analyzed in relation to plasma viral load (VL) and CD4 T lymphocytes during a 6-12-month interval when no antiretroviral therapy was taken. RESULTS: HLA-B*57 alone was a strong predictor of VL (P < 0.0001), but composite genetic profiles found in over 50% of patients consistently outperformed the individual component markers in multivariable analyses with or without adjustment for gender, race, age, and membership of clinical patient groups. Adolescents (n = 37) with a favorable combination of VL (< 1000 copies/ml) and CD4 T cell counts (> 450 x 10(6) cells/l) consistently had more positive (+1 to +2) than negative (-1 to -4) HLA and CCR scores compared with those (n = 56) with an unfavorable combination (VL > 16,000 copies/ml and CD4 cells < 450 x 10(6) cells/l) or the remainder (n = 134) of the cohort (overall P < 0.0001). CONCLUSION: A generalizable genetic scoring algorithm based on seven HLA class I and CCR markers is highly predictive of viremia and immunodeficiency in HIV-1-infected adolescents.

Adolescent↗

PubMed2002

Increased proliferation within T lymphocyte subsets of HIV-infected adolescents.

Proliferation within T lymphocyte subsets of HIV-infected adolescents was quantified by detection of Ki-67, a nuclear antigen found in cells in late G(1), S, or G(2) phases of the cell cycle. Median percentages and absolute counts of Ki-67(+) cells for all subsets tested (CD4 naive and memory, CD8 naive and memory) were significantly higher for HIV-infected adolescents compared to uninfected controls. CD8 naive cells of HIV-infected adolescents had the greatest increase in rate of proliferation and number of proliferating cells compared to uninfected controls. In HIV-infected adolescents, the percentage and absolute number of proliferating CD4 naive cells were considerably lower than corresponding values for the other subsets. CD4 percent correlated inversely with Ki-67 expression in CD4 memory, CD8 naive, and CD8 memory cells, while Ki-67 expression in CD4 and CD8 memory cells correlated directly with average CD38 molecules/CD8 cell and absolute number of CD8/CD38/HLA-DR cells, consistent with T cell activation. These results indicate that in adolescents, HIV infection is associated with increased proliferation within CD4 and CD8 naive and memory subsets. Proliferation within the CD8 naive subset was higher than that observed previously for HIV-infected adults, suggesting that adolescents have a greater ability to regenerate and/or expand CD8 naive cells. CD4 naive cells of HIV-infected adolescents had a low rate of proliferation, and the total number of CD4 naive cells was low, suggesting that regeneration and/or peripheral expansion are limited and may contribute to the reduced size of this subset. The Ki-67 assay provided new and useful information on in vivo lymphocyte proliferation in HIV-infected adolescents.

ADP-ribosyl Cyclase↗

PubMed2002

CCR2 and CCR5 genotypes in HIV type 1-infected adolescents: limited contributions to variability in plasma HIV type 1 RNA concentration in the absence of antiretroviral therapy.

In HIV-1-infected individuals, plasma viral RNA concentration as well as preservation of CD8+ naive T cells can vary by age. Host genetic factors previously shown to mediate HIV-1 pathogenesis in adults and children may operate differently in HIV-1-infected adolescents. Our PCR-based haplotyping of genetic variants at the loci encoding CC (beta) chemokine receptor 2 (CCR2) and CCR5 revealed nine haplotypes (designated A through G*2) in 179 seronegative and 228 seropositive adolescent participants from the Reaching for Excellence in Adolescent Care and Health (REACH) Study of the Adolescent Medicine and HIV/AIDS Research Network. The influence of CCR2-CCR5 haplotypes and genotypes on plasma HIV-1 RNA level was assessed in 207 AIDS-free seropositive individuals (mostly African-American females) who either did not receive therapy or had discontinued therapy for 6-12 months during initial follow-up between 1996 and 1999. The CCR2-64I-coding haplotype F*2 and the infrequent CCR5 Delta32-bearing haplotype G*2 had negligible impact on HIV-1 RNA level (p > 0.83) and CD4+ T cell counts (p > 0.30). In contrast, nine carriers of the E/E genotype had significantly higher (p = 0.007) plasma HIV-1 RNA level and slightly reduced CD4+ cell counts (p = 0.15) compared with those not carrying E/E or F*2 or G*2. The effect of E/E on HIV-1 RNA was stronger (p < 0.001) in a multivariable model adjusted for F*2 or G*2 (p = 0.45), race (p = 0.23), gender (p = 0.002), age (p = 0.26), and history of antiretroviral therapy (p < 0.001). Thus, among the major CCR2-CCR5 haplotypes/genotypes in chronically infected and predominantly African-American adolescents, only the E/E genotype appeared to influence early host-virus equilibration.

Acquired Immunodeficiency Syndrome↗