Joanna Dobroszycki

Selective Loss of Innate CD4+ Vα24 Natural Killer T Cells in Human Immunodeficiency Virus Infection

ABSTRACT Vα24 natural killer T (NKT) cells are innate immune cells involved in regulation of immune tolerance, autoimmunity, and tumor immunity. However, the effect of human immunodeficiency virus type 1 (HIV-1) infection on these cells is unknown. Here, we report that the Vα24 NKT cells can be subdivided into CD4+ or CD4− subsets that differ in their expression of the homing receptors CD62L and CD11a. Furthermore, both CD4+ and CD4− NKT cells frequently express both CXCR4 and CCR5 HIV coreceptors. We find that the numbers of NKT cells are reduced in HIV-infected subjects with uncontrolled viremia and marked CD4+ T-cell depletion. The number of CD4+ NKT cells is inversely correlated with HIV load, indicating depletion of this subset. In contrast, CD4− NKT-cell numbers are unaffected in subjects with high viral loads. HIV infection experiments in vitro show preferential depletion of CD4+ NKT cells relative to regular CD4+ T cells, in particular with virus that uses the CCR5 coreceptor. Thus, HIV infection causes a selective loss of CD4+ lymph node homing (CD62L+) NKT cells, with consequent skewing of the NKT-cell compartment to a predominantly CD4− CD62L− phenotype. These data indicate that the key immunoregulatory NKT-cell compartment is compromised in HIV-1-infected patients.

HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment

The immunology of vertical HIV transmission differs from that of adult infection in that the immune system of the infant is not fully matured, and the factors that influence the functionality of CD8+ T cell responses against HIV in children remain largely undefined. We have investigated CD8+ T cell responses in 65 pediatric subjects with vertically acquired HIV-1 infection. Vigorous, broad, and Ag dose-driven CD8+ T cell responses against HIV Ags were frequently observed in children who were older than 3 years of age and maintained CD4+ T cell counts >400 cells/μl. In contrast, younger age or a CD4+ T cell count <400 cells/μl was associated with poor CD8+ T cell responses and high HIV loads. Furthermore, subjects with a severely depleted and phenotypically altered CD4+ T cell compartment had circulating Gag-specific CD8+ T cells with impaired IFN-γ production. When viral load was not suppressed by antiviral treatment, subjects that fell below the putative age and CD4+ T cell count thresholds had significantly reduced CD8+ T cell responses and significantly higher viral loads. Thus, the data suggest that fully effective HIV-specific CD8+ T cell responses take years to develop despite an abundance of Ag in early life, and responses are further severely impaired, independent of age, in children who have a depleted or skewed CD4+ T cell compartment. The results are discussed in relation to differences between the neonatal and adult immune systems in the ability to respond to HIV infection.

The impact of early initiation of highly active antiretroviral therapy on the human immunodeficiency virus type 1-specific CD8 T cell response in children

This cross-sectional study investigated the effect of early highly active antiretroviral therapy (HAART) on human immunodeficiency virus (HIV) type 1-specific CD8 T cell responses in children. HIV-1-specific CD8 T cell responses were quantified using an enzyme-linked immunospot assay to measure interferon-gamma-secreting cells. HIV-1-infected children were classified by time of HAART initiation prior to age 1 year or after age 2 years as early (n=24) or late (n=28) treated. The magnitude and breadth of the HIV-1-specific CD8 T cell response was significantly lower in children receiving early compared with late HAART treatment (P=.0007 and.0001, respectively). However, total CD8 T cell responses in the early HAART treatment group did not differ significantly from those of age-matched non-HAART-treated controls (n=30). Thus, the reduced magnitude and breadth of the HIV-1-specific CD8 T cell response in early HAART-treated children is due to their younger age.

Haemophilus influenzae type b bacteremia in adults with AIDS and at risk for AIDS.

PURPOSE Our objective was to determine the number of cases of Haemophilus influenzae type b bacteremia in patients with and at risk for acquired immunodeficiency syndrome (AIDS) from January 1983 to June 1991 at a municipal hospital in Bronx, New York. PATIENTS AND METHODS We reviewed blood culture records of adult patients admitted to North Central Bronx Hospital from January 1983 to June 1991 to identify cases of bacteremic H. influenzae type b disease. The hospital charts and admission chest radiographs of bacteremic patients were then reviewed. RESULTS Ten of 15 cases of adult H. influenzae type b bacteremia occurred in patients with AIDS or who were at risk for AIDS. Seven had AIDS at presentation. Nine were active or former intravenous drug users (IVDUs). All 10 cases were associated with a respiratory source, and five of the 10 patients also had H. influenzae type b isolated from sputum. All H. influenzae type b strains were negative for beta-lactamase. CONCLUSIONS Human immunodeficiency virus-positive IVDUs may be at increased risk for bacteremic H. influenzae type b infections. Empiric antibiotic regimens for community-acquired pneumonia in these patients should include appropriate antibiotics for the treatment of H. influenzae type b. In addition, these patients may be candidates for conjugate H. influenzae type b vaccine trials.

Pregnancy in women with perinatally acquired HIV-infection: outcomes and challenges.

This is a retrospective comparison of pregnant women with perinatally acquired HIV-infection (PAH) with a cohort of pregnant women with behaviorally acquired HIV-infection (BAH). PAH cases (11 women) included all pregnant adolescents followed at our HIV clinic from January 2000 to January 2009. BAH cases (27 women) were randomly selected from all deliveries within the study period at the same institution. Demographics, mode of delivery, CD4+ counts, and viral loads (VLs) before, during, and six months postpartum, as well as neonatal outcomes, were reviewed. CD4 counts were significantly lower in the PAH group. VLs were statistically higher in the PAH group. VLs were undetectable at delivery in 60% of the PAH group compared with 88% of the BAH group. No cases of vertical transmission occurred. PAH women may be at a higher risk for HIV-related disease progression. This may increase vertical transmission risks. Further studies and interventions with this growing population are warranted.

Partial treatment interruption of protease inhibitor-based highly active antiretroviral therapy regimens in HIV-infected children.

Summary: Treatment guidelines for HIV-infected children recommend using combinations of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). Successful suppression of HIV replication and adherence to these regimens are often suboptimal because of multiple factors. For patients with detectable viremia and limited treatment options, therapy simplification consisting of RTIs, referred to as partial treatment interruption (PTI), may represent a temporizing option. We describe a cohort of 26 HIV-infected children who underwent treatment simplification by discontinuing the PI and continuing therapy with 2 or more RTIs. The subjects, who were identified retrospectively, were followed for a period of 24 to 96 weeks. Data collected included clinical information, viral load, and CD4+T lymphocyte percentage (CD4%) at baseline and 24, 48, and 96 weeks after PTI. Twenty-six, 21, and 11 patients were evaluated at 24, 48, and 96 weeks, respectively. No child had Centers for Disease Control and Prevention-defined disease progression, and there were no significant changes in viral loads (P > 0.5) across all study intervals after interruption of the PIs. Although most children maintained a CD4% > 15%, comparisons of CD4% at 24 and 48 weeks demonstrated a statistically significant decrease compared with baseline. Therapy simplification by PTI may provide a practical option in patients intolerant of or failing PI-based highly active antiretroviral therapy.

FcγRIIa polymorphism in human immunodeficiency virus-infected children with invasive pneumococcal disease

Invasive pneumococcal disease (IPD) occurs frequently in HIV-infected children and adults. Defects in complement function, opsonic capsular antibodies, and Fc receptor antibody-mediated phagocytosis could contribute to impaired host defense against Streptococcus pneumoniae. The objective of this study was to define the distribution of the three FcγRIIa genotypes in HIV+ children, including those with IPD. Forty-eight HIV+ Hispanic children, including eight with IPD, followed at Bronx-Lebanon Hospital Center, Bronx, New York, nine HIV+ adults with IPD, and 56 HIV- Hispanic control subjects were studied. The children and adults were identified retrospectively except for one child who developed IPD during the study. FcγRIIa genotypes were determined by PCR amplification of the FcγRIIa locus from genomic DNA samples and hybridization of the PCR products with allele-specific oligonucleotides. Naturally occurring serum antibodies reactive with four pneumococcal polysaccharide serotypes were determined by ELISA in seven of eight children with IPD. There were no statistical differences in FcγRIIa genotypes between HIV+ children with and without IPD, HIV+ adults with IPD, or HIV- Hispanics. The predominant IgG subclass of pneumococcal polysaccharide binding antibodies in the seven HIV+ children with IPD studied was IgG1. The distribution of FcγRIIa genotypes in HIV+ children with and without IPD is similar to that of the normal Hispanic population. The prospect of passive immunotherapy with specific anticapsular antibodies might be a promising alternative for the treatment and/or prevention of IPD in HIV+ children and other immunodeficient groups.

Immunodominance of HIV-1 specific CD8+ T-cell responses is related to disease progression rate in vertically infected adolescents.

Background HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. Methodology/Principal Findings In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. Conclusions/Significance Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions.

Impact of HIV-1 infection and pregnancy on maternal health: comparison between perinatally and behaviorally infected young women.

Background The introduction of combination antiretroviral therapy has resulted in improved survival and quality of life for individuals infected with the human immunodeficiency virus (HIV). There is, as expected, a growing population of perinatally HIV-infected women who are, have been, or will become pregnant. We describe a large cohort of perinatally infected women, compare it with a similar age-matched behaviorally HIV-infected group, and examine factors affecting maternal and infant health. Methods We reviewed the records of 30 perinatally infected women who gave birth at two hospitals between January 2000 and December 2011. The comparison group comprised behaviorally infected women who delivered at these hospitals during the same period. The outcome measures were differences in CD4 counts and viral load between the cohorts, and comparisons of maternal morbidity, mortality, and mother-to-child HIV transmission. Results Median CD4 counts were significantly lower in the perinatal group before, during, and after pregnancy. The median viral load was significantly higher in the perinatal group. Interval prepregnancy to post partum viral load decline was also greater in the behavioral group. Viral load decreases in the perinatal population were not sustained in the post partum period, at which time viral load trended back to prepregnancy levels. There was one mother-to-child HIV transmission in a perinatally infected woman. Over an extended 4 years of follow-up, there were four deaths in the perinatal group and none in the behavioral group. Conclusion After delivery, the differences between perinatally and behaviorally infected mothers accentuate, with immunologic deterioration in the former group. The perinatal population may require novel management strategies to ensure outcomes comparable with those observed in the behavioral group.

Profile of darunavir in the treatment of HIV-infected pediatric and adolescent patients.

The introduction of protease inhibitors (PI) containing antiretroviral regimens in the treatment of HIV infection in infants, children, and adolescents has dramatically decreased morbidity and mortality. Darunavir, the latest PI to be FDA approved for pediatric patients older than 6 years and currently the preferred PI for use in adult patients, was added as an alternative PI for use in children based on a combination of data from both adult and pediatric trials. This review of darunavir in the treatment of HIV-infected children and adolescents looks at the major published clinical trials findings, pharmacokinetic and resistance studies, and preliminary data on use in younger children.