Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
HLA class I; Allele frequency; HIV-1 control; African American
To examine the prevalence and biopsychosocial predictors of sub-optimal virologic response to highly active antiretroviral therapy (HAART) among human immunodeficiency virus (HIV)-infected adolescents.
Population-based cohort study.
Sixteen academic medical centers across thirteen cities in the United States.
One hundred and fifty four HIV-infected adolescents who presented for at least two consecutive visits after initiation of HAART.
Main Outcome Measures
Viral load (plasma concentration of HIV RNA), CD4+ T-lymphocyte count.
Of the 154 adolescents enrolled in the study, 50 (32.5%) demonstrated early and sustained virologic suppression while receiving HAART. The remaining 104 adolescents (67.5%) had a poor virologic response. Adequate adherence (>50%) to HAART—reported by 70.8% of respondents—was associated with a 60% reduced odds of suboptimal virologic suppression in a multivariable logistic regression model (adjusted odds ratio = 0.4; 95% confidence interval : 0.2 – 1.0). Exposure to sub-optimal antiretroviral therapy (ART) prior to HAART, on the other hand, was associated with more than a two-fold increased odds of sub-optimal virologic response (adjusted odds ratio = 2.6; 95% confidence interval: 1.1 – 5.7).
Fully two-thirds of HIV-infected adolescents in the current study demonstrated a sub-optimal virologic response to HAART. Non-adherence and prior single or dual ART were associated with subsequent poor virologic responses to HAART. These predictors of HAART failure echo findings in pediatric and adult populations. Given the unique developmental stage of adolescence, age-specific interventions are indicated to address high rates of non-adherence and therapeutic failure.
HIV; Adolescent; Antiretroviral Therapy; Highly Active; Adherence; Viral Load; CD4 Lymphocyte Count
We report evidence of low bone mass in behaviorally human immunodeficiency virus (HIV)–infected young men on antiretroviral therapy with a relatively recent diagnosis of HIV infection, compared with seronegative controls.
Background. Peak bone mass is achieved in adolescence/early adulthood and is the key determinant of bone mass in adulthood. We evaluated the association of bone mass with human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) during this critical period among behaviorally HIV–infected young men and seronegative controls.
Methods. HIV-positive men (N = 199) and HIV-negative controls (N = 53), ages 14–25 years, were studied at 15 Adolescent Trials Network for HIV/AIDS Interventions sites. HIV-positive participants were recruited on the basis of ART status: ART-naive (N = 105) or on a regimen containing a nonnucleoside reverse transcriptase inhibitor (NNRTI; N = 52) or protease inhibitor (PI; N = 42). Bone mineral density (BMD) and content (BMC) and body composition were measured by dual-energy X-ray absorptiometry (DXA). Results were compared across groups by linear modeling. Bone results were adjusted for race, body mass index (BMI), and type of DXA (Hologic/Lunar).
Results. The HIV-positive and HIV-negative groups had comparable median age (21 years) and racial/ethnic distribution. Median times since HIV diagnosis were 1.3, 1.9, and 2.2 years in the ART-naive, NNRTI, and PI groups, respectively (P = .01). Total and regional fat were significantly lower in the ART-naive group compared with seronegative controls. Mean BMD and Z scores were generally lower among HIV-positive participants on ART, particularly in the PI group. Average Z scores for the spine were below zero in all 4 groups, including controls.
Conclusions. Young men on ART with a relatively recent diagnosis of HIV infection have lower bone mass than controls. Longitudinal studies are required to determine the impact of impaired accrual or actual loss of bone during adolescence on subsequent fracture risk.
Future HIV vaccine efficacy trials with adolescents will need to ensure that participants comprehend study concepts in order to confer true informed assent. A Hepatitis B vaccine trial with adolescents offers valuable opportunity to test youth understanding of vaccine trial requirements in general.
Youth reviewed a simplified assent form with study investigators and then completed a comprehension questionnaire. Once enrolled, all youth were tested for HIV and confirmed to be HIV-negative.
123 youth completed the questionnaire (mean age=15 years; 63% male; 70% Hispanic). Overall, only 69 (56%) youth answered all six questions correctly.
Youth enrolled in a Hepatitis B vaccine trial demonstrated variable comprehension of the study design and various methodological concepts, such as treatment group masking.
Adolescents and youth ages 15–24 are one of the populations most impacted by the global HIV epidemic with an estimated 50% of new infections occurring in this age group. They are thus one of the prime populations for targeting behavioral and biomedical preventions. However, the dynamics of the HIV epidemic in youth vary widely by geographic region as well as risk behavior profiles. There are also biological and neurodevelopmental considerations that must be considered in the development, testing and ultimate dissemination of HIV prevention interventions. These concepts are broadly discussed here.
HIV/AIDS; Epidemiology; Adolescents
In this randomized, double-blind, placebo-controlled trial of human immunodeficiency virus–infected youths aged 18–25, vitamin D3, 50000 IU once monthly for 3 months decreased parathyroid hormone in participants treated with tenofovir-containing antiretroviral regimens but not in those participants whose regimens did not contain tenofovir.
Background. The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF).
Methods. This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18–25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo.
Results. At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, −7.9 and −6.2 pg/mL; P = .031 and .053, respectively).
Conclusions. In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration.
Clinical Trials Registration. NCT00490412.
Several studies have assessed risk factors associated with herpes simplex virus-2 (HSV-2) prevalence in adults; however, few have focused on HSV-2 incidence, particularly in adolescents. The objective of this study was to determine HSV-2 prevalence and incidence and associated risk factors in a HIV-1-positive and at risk HIV-1-negative adolescent population.
Sera were tested for HSV-2 antibodies in 518 adolescents in the Reaching for Excellence in Adolescent Care and Health (REACH) cohort at baseline and again at the final follow-up visit. Prevalence at baseline and incidence (per person years) of HSV-2 infection were calculated. Furthermore, among HIV-1-positive individuals, a subgroup analysis was performed to assess risk factors for HSV-2 infection. Conditional logistic regression was used to estimate odds ratios (OR) and p-values (p) for associations between CD4+ T-cell (CD4+) count, HIV-1 viral load (VL), and HSV-2 acquisition, adjusting for antiretroviral therapy use, other sexually transmitted infections, gender, race, and number of sexual partners.
At baseline, 179 (35%) subjects were HSV-2 positive, with an additional 47 (16%) new cases being identified during a median follow-up time of 1.95 years and an incidence rate of 7.35 cases per 100 person years (py). Several risk factors were associated with HSV-2 prevalence (being female, non-Hispanic, uncertainty of sexual preference, and HIV-1 positive) and incidence (using drugs, alcohol, and number of new sexual partners). Among HIV-1 positives, an increase in CD4+ count by 50 cell/mm3 (OR, 1.17; 95% CI 1.04–1.31, p=0.008) was associated with HSV-2 acquisition.
The high prevalence and incidence of HSV-2 infection among adolescents, compared to the general population at this age group suggests a critical need for screening and preventive programs among this targeted group.
HIV-1; HSV-2; CD4+ count; adolescents
HIV-infected youth are at risk of hepatitis B (HBV) infection and should be vaccinated. Previous reports suggest reduced response to standard HBV vaccine regimens.
HIV-infected youth, age 12 to <25 years, were randomly assigned to one of three treatment arms: Arm 1: Engerix B®, 20 mcg HBsAg; Arm 2: Engerix B®, 40 mcg; and Arm 3: Twinrix®, 20mcg HBsAg combined with 720 ELU hepatitis A antigen. Vaccines were administered at weeks 0, 4 and 24.
Characteristics of evaluable patients (n=336) at entry were similar in the study arms. At enrollment, median CD4+ T-cell count was 460 cells/mm3 (IQR: 305 to 668); 13% were < 200 cells/mm3. Among Engerix B®, 20 mcg recipients, 60.4% responded to vaccine (HBsAb ≥ 10 IU/mL at week 28). Improved vaccine response was seen in recipients of Engerix B®, 40 mcg, (73.2%, vs. Arm 1, p=0.04) and Twinrix® (75.4%, vs. Arm 1, p=0.02). In multivariate analysis, only baseline CD4+ T-cell count and study arm were independent predictors of vaccine response.
In HIV-infected youth, a three dose vaccination regimen with Engerix B®, 40 mcg, or Twinrix® and higher baseline CD4+ T-cell counts were independently associated with improved vaccine response.
HIV; Hepatitis B Vaccination; Adolescents; Engerix B; Twinrix
To evaluate the stability and heterogeneity of cytokine and chemokine profiles in 80 youth with and without HIV-1 infection, we tested plasma samples at repeated visits without antiretroviral therapy. Among nine analytes that were quantified using multiplexing assays, interleukin 10 (IL-10), IL-18, and soluble CD30 persistently showed a positive correlation with HIV-1 viral load (Spearman ρ = 0.40–0.59, p < 0.01 for all). A negative correlation with CD4+ T cell counts (ρ = −0.40 to −0.60, p < 0.01 for all) was also persistent for the three analytes. Analyses restricted to 48 AIDS-free youth (96 visits) yielded similar findings, as did multivariable models in which race, sex, age, body mass index, and time interval between visits were treated as covariates. These relationships reflected two novel features observed for all three analytes. First, their presence in plasma was relatively stable between visits (ρ = 0.50–0.90, p < 0.03), regardless of HIV-1 infection status. Second, pairwise correlation was strong and persistent in HIV-1-seropositive youth (ρ = 0.40–0.59, p < 0.01), but not in HIV-1, seronegatives (p > 0.13). Additional analytes, especially eotaxin/CCL11 and SDF-1β/CXCL12, had no correlation with HIV-1-related outcomes despite their stability between visits. Overall, circulating IL-10, IL-18, and soluble CD30 could partially track unfavorable responses to HIV-1 infection in youth. These markers of persistent immune activation are individually and collectively indicative of HIV-1 pathogenesis.
Multiple studies have shown excellent response rates after hepatitis B immunization in youth; however, one previous study conducted in urban youth demonstrated poor responses.
Urban youth, ages 12-17 years, at participating Adolescent Medicine Trials Network for HIV/AIDS Interventions Clinical/Research (ATN) sites were randomized to receive either two doses of Recombivax HB (10mcg hepatitis B surface antigen) or Twinrix (20mcg hepatitis B surface antigen and 720 EL.U hepatitis A antigen) at 0 and 24 weeks. Safety data were collected and antibody measures performed at 0, 28 and 76 weeks.
123 subjects were enrolled and 102 had week 28 serum samples available for antibody measure. A positive response (serum antibody ≥ 10mIU/mL) to hepatitis B antigen was documented in 41/47 (87.2%; 95% confidence interval (CI) 74.3%-95.2%) Recombivax HB recipients and in 52/55 (94.6%; 95% CI 84.9%-98.9%) Twinrix recipients (p=.295). In an adjusted analysis, those identified as Hispanic ethnicity (N=86) were more likely to have a positive response (odds ratio 7.38, 95% confidence interval 1.56-34.95; p=0.0018); whereas those who identified as not heterosexual (N=9) were less likely to respond (odds ratio=0.12, 95%CI, 0.02-0.74). The majority of youth in the Twinrix arm were hepatitis A antibody positive at baseline (26/51; 51%); however, 24/25 hepatitis A antibody negative youth responded to the hepatitis A component. Both vaccines were safe.
Response rate to two doses of Recombivax HB in urban youth is lower than previous studies suggest. The factors associated with diminished response are not known.
Adolescents; hepatitis B; Vaccination; Immunogenicity
HIV-1-positive patients clear the human papillomavirus (HPV) infection less frequently than HIV-1-negative. Datasets for estimating HPV clearance probability often have irregular measurements of HPV status and risk factors. A new transitional probability-based model for estimation of probability of HPV clearance was developed to fully incorporate information on HIV-1-related clinical data, such as CD4 counts, HIV-1 viral load (VL), highly active antiretroviral therapy (HAART), and risk factors (measured quarterly), and HPV infection status (measured at 6-month intervals).
Methodology and Findings
Data from 266 HIV-1-positive and 134 at-risk HIV-1-negative adolescent females from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort were used in this study. First, the associations were evaluated using the Cox proportional hazard model, and the variables that demonstrated significant effects on HPV clearance were included in transitional probability models. The new model established the efficacy of CD4 cell counts as a main clearance predictor for all type-specific HPV phylogenetic groups. The 3-month probability of HPV clearance in HIV-1-infected patients significantly increased with increasing CD4 counts for HPV16/16-like (p<0.001), HPV18/18-like (p<0.001), HPV56/56-like (p = 0.05), and low-risk HPV (p<0.001) phylogenetic groups, with the lowest probability found for HPV16/16-like infections (21.60±1.81% at CD4 level 200 cells/mm3, p<0.05; and 28.03±1.47% at CD4 level 500 cells/mm3). HIV-1 VL was a significant predictor for clearance of low-risk HPV infections (p<0.05). HAART (with protease inhibitor) was significant predictor of probability of HPV16 clearance (p<0.05). HPV16/16-like and HPV18/18-like groups showed heterogeneity (p<0.05) in terms of how CD4 counts, HIV VL, and HAART affected probability of clearance of each HPV infection.
This new model predicts the 3-month probability of HPV infection clearance based on CD4 cell counts and other HIV-1-related clinical measurements.
The goal of this study was to determine the nature and prevalence of abnormalities in lipids, glucose metabolism, and body composition in behaviorally HIV-infected young women and their relationship to different classes of antiretroviral therapy (ART) regimens.
We conducted a cross-sectional multicenter study in behaviorally infected women ages 12-24 years (HIVpos; N=173) and seronegative controls (HIVneg; N=61). HIVpos women were categorized as ART-naïve (N=85), on a non-nucleoside reverse transcriptase inhibitor-containing regimen (NNRTI; N=33), on a protease inhibitor-containing regimen (PI; N=36), or on a non-NNRTI/non-PI containing regimen (N=19). Measurements included fasting lipids; glucose and insulin before and 2 hours after an oral glucose challenge; high-sensitivity C-reactive protein (hsCRP); anthropometry; fat distribution (dual energy X-ray absorptiometry); and ART and medical histories. Race-adjusted results were compared across groups and within HIVpos groups.
The median age was 20 (range 14-24) years. 77% of HIVpos were African American, 35% smoked cigarettes, and 32% reported exercising regularly. More than 40% had a BMI ≥25 kg/m2. Triglycerides; total, HDL, and non-HDL cholesterol; and hsCRP differed significantly among groups, with higher levels most common among those on ART. Indices of glucose metabolism did not differ among groups. In general, cholesterol, hsCRP, and indices of glucose metabolism worsened as BMI increased.
Obesity, dyslipidemia, and inflammation were prominent in HIV-infected adolescent women and, coupled with other risk factors, may accelerate the lifetime risk of cardiovascular disease and other adverse events. These results underscore the need for a multifaceted approach to addressing risk reduction in this population.
adolescent; women; obesity; dyslipidemia; inflammation
Immunological and clinical outcomes can vary considerably at the individual and population levels during both treated and untreated HIV-1 infection. Cytokines encoded by the interleukin-10 gene (IL10) family have broad immunomodulatory function in viral persistence, and several SNPs in the IL10 promoter sequence have been reported to influence pathogenesis or acquisition of HIV-1 infection.
We examined 104 informative SNPs in IL10, IL19, IL20, IL24, IL10RA and IL10RB among 250 HIV-1 seropositive and 106 high-risk seronegative African American adolescents in the REACH cohort. In subsequent evaluation of five different immunological and virological outcomes related to HIV-1 infection, 25 SNPs were associated with a single outcome and three were associated with two different outcomes. One SNP, rs2243191 in the IL19 open reading frame (Ser to Phe substitution) was associated with CD4+ T-cell increase during treatment. Another SNP rs2244305 in IL10RB (in strong linkage disequilibrium with rs443498) was associated with an initial decrease in CD4+ T-cell by 23±9% and 29±9% every 3 months (for AA and AG genotypes, respectively, compared with GG) during ART-free period. These associations were reversed during treatment, as CD4+ T-cell increased by 31±0.9% and 17±8% every 3 months for AA and AG genotype, respectively.
In African Americans, variants in IL10 and related genes might influence multiple outcomes of HIV-1 infection, especially immunological response to HAART. Fine mapping coupled with analysis of gene expression and function should help reveal the immunological importance of the IL10 gene family to HIV-1/AIDS.
The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial.
HIV-positive and high-risk HIV-negative female adolescents were enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) longitudinal cohort study. At each semi-annual clinical visit, cervical lavage samples were tested for 30 HPV types. Type-specific and carcinogenic risk-specific HPV prevalence and incidence were compared in 373 eligible participants: 146 HIV-negative female adolescents with a median follow-up of 721.5 [IQR: 483-1301] days and 227 HIV-positive female adolescents. Of the 227 HIV-positive participants, a fixed set (n = 100) were examined both before and after HAART initiation; 70 were examined only before HAART initiation; and 57 were examined only after HAART initiation, with overall median follow-up of 271 [IQR: 86.5-473] and 427.25 [IQR: 200-871] days respectively for before and after HAART initiation.
Of the 373 eligible participants, 262 (70%) were infected with at least one type of HPV at baseline, and 78 of the remaining 111 (70%) became infected with at least one type of HPV by the end of the study. Overall, the incidence and prevalence of HPV types 58, 53/66, 68/70, and 31/33/35 were much higher than the established carcinogenic and HPV vaccine types 16 and 18, especially in HIV-positive females both before and after HAART initiation. Baseline prevalence for individual high-risk HPV types ranged, depending on type, from 0.7-10%, 1-17%, and 1-18% in the HIV-negative group, the HIV-positive before HAART initiation group, and the HIV-positive after HAART initiation group, respectively. Likewise, the incidence ranged, depending on HPV type, from 0.64-9.83 cases/100 PY, 3.00-12.80 cases/100 PY, and 1.49-17.05 cases/100 PY in the three groups, respectively. The patterns of each HPV type infection, clearance, and persistence did not differ considerably before or after the introduction of HAART and were clearly independent of CD4+ change within the short post-HAART follow-up period.
HAART did not immediately affect the incidence of type-specific HPV infections within a short-period follow-up; however, future studies are warranted in larger populations to evaluate HAART's impact over longer periods.
The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in African Americans has not been established. We examined the effects of the HLA-A and HLA-B alleles and supertypes on the outcomes of HIV-1 clade B infection among 338 African American women and adolescents. HLA-B58 and -B62 supertypes (B58s and B62s) were associated with favorable HIV-1 disease control (proportional odds ratio [POR] of 0.33 and 95% confidence interval [95% CI] of 0.21 to 0.52 for the former and POR of 0.26 and 95% CI of 0.09 to 0.73 for the latter); B7s and B44s were associated with unfavorable disease control (POR of 2.39 and 95% CI of 1.54 to 3.73 for the former and POR of 1.63 and 95% CI of 1.08 to 2.47 for the latter). In general, individual alleles within specific B supertypes exerted relatively homogeneous effects. A notable exception was B27s, whose protective influence (POR, 0.58; 95% CI, 0.35 to 0.94) was masked by the opposing effect of its member allele B*1510. The associations of most B supertypes (e.g., B58s and B7s) were largely explained either by well-known effects of constituent B alleles or by effects of previously unimplicated B alleles aggregated into a particular supertype (e.g., B44s and B62s). A higher frequency of HLA-B genotypic supertypes correlated with a higher mean viral load (VL) and lower mean CD4 count (Pearson's r = 0.63 and 0.62, respectively; P = 0.03). Among the genotypic supertypes, B58s and its member allele B*57 contributed disproportionately to the explainable VL variation. The study demonstrated the dominant role of HLA-B supertypes in HIV-1 clade B-infected African Americans and further dissected the contributions of individual class I alleles and their population frequencies to the supertype effects.
This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV.
In a recent genome-wide association study of HIV-1-infected individuals in the Euro-CHAVI cohort, viral load set-point was strongly associated with genotypes defined by two SNPs (rs9264942 and rs2395029) within the human MHC region on chromosome 6. We attempted to confirm this finding in African-Americans and assess if these SNPs are in linkage disequilibrium (LD) with HLA class I alleles that mediate innate and adaptive immunity.
Our analyses relied on 121 African American adolescents with chronic HIV-1 infection and quarterly immunological and virological outcome measures in the absence of therapy.
PCR-based techniques were used to genotype two SNPs along with HLA class I alleles. Their associations with HIV-1 viral load set-point and longitudinal CD4+ and CD8+CD38+ T-cell counts were tested in univariate and multivariate models.
The CC genotype at rs9264942 was associated with reduced viral load but not with immunological outcomes or category of disease control. Consistent associations of HLA-B*57 (mostly B*5703) with favorable virological and immunological outcomes were observed, but not rs2395029G allele at the HCP5 locus, which is in absolute linkage disequilibrium with B*5701 (in individuals of European descent), and not B*5703.
While rs9264942 and B*57 (but not rs2395029G) are clearly associated with control of viral load set-point among African-Americans, fine-mapping of MHC SNPs in populations of African and European descent should help reveal the true variants and the underlying functional mechanisms.
HIV-1; genetics; viral load; African American
To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV−) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration ≥ 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10–1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV+ youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-009-0720-z) contains supplementary material, which is available to authorized users.
There is a continuing need to evaluate sustainable interventions for prevention of mother-to-child transmission (MTCT) of HIV type 1. We evaluated different concentrations (0.25%, 1%, and 2%) of chlorhexidine (CHX) for perinatal maternal and infant washes to identify the maximum tolerable concentration of CHX for such an intervention.
Women were enrolled during their third trimester at the maternity unit of the Chris Hani Baragwanath Hospital in Soweto, South Africa, and perinatal maternal and infant washes were completed. Subjective maternal symptoms as well as infant examinations were used to assess tolerability of the washes.
The 0.25% concentration of CHX was well tolerated by the mothers (n = 29). Ten of 79 women (13%) with 1% CHX washes complained of mild vaginal area burning or itching, and washes were stopped in 5 (6%). Twenty-three of 75 women (31%) in the 2% CHX wash group had subjective complaints, and the washes were stopped in 12 (16%). There were no clinical indications of toxicity of the CHX washes among infants.
A 1% solution of CHX appears to be a safe and tolerable concentration of CHX for consideration in an MTCT prevention trial.
vertical transmission; chlorhexidine; peripartum microbicide washes
Understanding host factors modulating immunity to Neisseria gonorrhoeae infection may benefit work on vaccine development.
We analyzed longitudinal data collected from 485 male and female adolescents to determine genetic correlates of genital gonorrhea. Cytokine data from 388 females were analyzed to assess immunologic markers of gonorrhea and their relationship to genetic correlates.
The T-G haplotype defining interleukin-2 (IL-2) gene promoter and intron 1 polymorphisms (−330T and −166G) was more frequently found in individuals who had gonorrhea (relative odds = 3.2, P = 0.01). Among 3 endocervical cytokines measured, IL-10 and IL-12 concentrations were higher and IL-2 lower when gonorrhea was detected. The decrease in endocervical IL-2 after gonorrhea acquisition was mostly restricted to subjects with the IL2 T-G haplotype, which may reflect involvement of a pathogen-specific and genetically mediated mechanism for differential IL-2 responses at genital mucosa. In addition, 2 human leukocyte antigen variants (Cw*04 and DQB1*05) were also independently associated with gonorrhea (adjusted relative odds = 1.9 and 0.5, respectively; P <0.05 for both).
Confirmation of immunogenetic correlates of gonorrhea in larger cohorts may be useful in guiding further research on both innate and adaptive immune responses to N. gonorrhoeae.
The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects ≥18 to <25 years old receiving (≥28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC0-24), maximum concentration of drug in serum (Cmax), concentration at 24 h postdose (C24), and total apparent oral clearance (CL/F) values were 35,971 ng·hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC0-24, Cmax, C24, and CL/F values were 2,762 ng·hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P ≤ 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir Cmax and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.
Differential protein targeting by HIV-specific CD8 T cells is associated with disparate plasma viral loads; however, it is unclear if the quality of these responses differs depending upon the specificity of the targeted epitopes.
We examined HIV-specific CD8 T-cell responses in HIV-infected adolescents carrying either an HLA class I allele associated with a favorable prognosis (HLA-B*57) or an allele associated with usual disease progression (HLA-B*35 or HLA-B*53) using interferon-γ ELISpot and ICS assays.
In an interferon-γ ELISpot assay, p24 was the dominant protein targeted by B*57 carriers while responses to Nef dominated in B*35 or B*53 positive carriers. This differential protein targeting did not change during 4 years of follow-up. In these chronically infected adolescents, there were no significant differences in the quality of the immunodominant T-cell responses between the B*57 and B*35/B*53 carriers as measured by peptide avidity, degranulation, and immune memory markers. There was a trend towards higher expression of interleukin-2 from B*57-KF11 restricted CD8 T cells although this difference was not significant. Nevertheless both B*57 and B*35/53-restricted responses were relatively potent as reflected by the propensity of CD8 T cells to escape in p24 and Nef, respectively.
Differential protein targeting rather than the quality of T-cell responses appears to be a major distinguishing feature of HIV-specific CD8 T cells induced in B*57 carriers. These data suggest that viral fitness costs associated with CD8 T-cell pressure is an important factor determining differences in the viral load among HIV-infected patients.
adolescents; CD8 T-cells; Gag; HIV-1; HLA-Class I; Nef
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/mm3, respectively. Only 8.1% of subjects had CD4+-T-cell counts below 200 cells/mm3, 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.
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.