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Papers by Stephen Spector

The Pediatric Infectious Disease Journal, 1996

The clinical manifestations of HIV infection in children involve a broad spectrum of conditions r... more The clinical manifestations of HIV infection in children involve a broad spectrum of conditions ranging from mild symptoms to AIDS. Knowledge of the disease and survival patterns of these children are needed to plan for future needs and develop baseline information to evaluate newer prophylactic or therapeutic management options. To identify AIDS-defining conditions and estimate post-AIDS diagnosis survival among HIV-infected children. Disease patterns and survival after the diagnosis of AIDS-defining conditions were studied in 126 children who were identified through a multisite university-based active surveillance system in California from January, 1989, through August, 1993. Hospital medical records were periodically reviewed and data were abstracted onto standardized forms designed for pediatric HIV surveillance. We determined the length of survival between AIDS diagnosis and death and evaluated the impact of disease patterns on survival using Kaplan-Meier's product-limit method and Cox proportional hazards regression. The median age at diagnosis was 13 months for children with perinatally acquired infection and 101.5 months for children infected through other routes of transmission. Pneumocystis carinii pneumonia and lymphoid interstitial pneumonia were the most common AIDS-defining conditions among perinatal cases, whereas the disease patterns observed among nonperinatal cases were more varied. The median postdiagnosis survival for the cohort was 26 months. Survival time did not differ significantly by race/ethnicity, sex or route of transmission. Respiratory candidiasis and wasting syndrome had significant negative impact on survival but P. carinii pneumonia was not associated with shorter survival. Zidovudine or other antiviral therapies was associated with increased survival.

Journal of Acquired Immune Deficiency Syndromes, Jun 1, 2019

Journal of Virology, 1994

Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 v... more Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine (AZT). Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy,...

Journal of Virology, 1999

The impact of cytomegalovirus (CMV) on human immunodeficiency virus type 1 (HIV-1) disease progre... more The impact of cytomegalovirus (CMV) on human immunodeficiency virus type 1 (HIV-1) disease progression has been controversial. In this study, we sought to determine if CMV viral load is independent of HIV-1 viral load in predicting CMV disease and survival. Our findings indicate that in patients with advanced AIDS, CMV DNA load is an independent marker of CMV disease and survival and is more predictive than HIV-1 RNA load. Moreover, patients who respond to preemptive therapy with oral ganciclovir, with resulting undetectable levels of CMV DNA, in their plasma, have a significantly lower risk of developing CMV disease and higher rates of survival, despite stable or increasing HIV-1 RNA loads. These data provide support for CMV as an independent risk factor for mortality in persons with advanced AIDS and further suggest that effective preemptive therapy for CMV can improve patient survival rates.

ABSTRACTBackgroundFew studies have evaluated the association between pre-existing vitamin D defic... more ABSTRACTBackgroundFew studies have evaluated the association between pre-existing vitamin D deficiency (VDD) and incident TB. We assessed the impact of baseline vitamin D on TB risk.MethodsWe assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6751 household contacts of TB patients in Peru. We also conducted a one-stage individual participant data meta-analysis searching PubMed and Embase for studies of vitamin D and TB until December 31, 2017. We included studies that assessed vitamin D before TB diagnosis. We defined VDD as 25–(OH)D <50 nmol/L, insufficiency as 50–75 nmol/L and sufficiency as >75nmol/L. We estimated the association between vitamin D and incident TB using conditional logistic regression in the Peru cohort and generalized linear mixed models in the meta-analysis.FindingsIn Peru, baseline VDD was associated with a statistically insignificant increase in incident TB (aOR 1·70, 95% CI 0·84–3·46; p=0·14). We identified se...

Advanced Materials, 2018

To improve human immunodeficiency virus (HIV) treatment and prevention, therapeutic strategies th... more To improve human immunodeficiency virus (HIV) treatment and prevention, therapeutic strategies that can provide effective and broad‐spectrum neutralization against viral infection are highly desirable. Inspired by recent advances of cell‐membrane coating technology, herein, plasma membranes of CD4+ T cells are collected and coated onto polymeric cores. The resulting T‐cell‐membrane‐coated nanoparticles (denoted as “TNPs”) inherit T cell surface antigens critical for HIV binding, such as CD4 receptor and CCR5 or CXCR4 coreceptors. The TNPs act as decoys for viral attack and neutralize HIV by diverting the viruses away from their intended host targets. This decoy strategy, which simulates host cell functions for viral neutralization rather than directly suppressing viral replication machinery, has the potential to overcome HIV genetic diversity while not eliciting high selective pressure. In this study, it is demonstrated that TNPs selectively bind with gp120, a key envelope glycoprot...

Clinical Infectious Diseases, 2017

Clinical Infectious Diseases, 2016

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistanc... more Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 18, 2015

Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency... more Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccin...

The Journal of infectious diseases, 2015

The mechanism of myeloid dendritic cell (mDC)-mediated impaired T-cell function was investigated ... more The mechanism of myeloid dendritic cell (mDC)-mediated impaired T-cell function was investigated during human immunodeficiency virus type 1 (HIV-1) infection. HIV or gp120 were found to inhibit lipopolysaccharide-induced mDC maturation and cause defects in allogeneic T-cell proliferation, interleukin 2 and interferon γ (IFN-γ) production, and phosphorylated STAT1 expression. gp120-treated mDCs downregulated autologous T-cell proliferation and IFN-γ production against a peptide pool consisting of cytomegalovirus, Epstein-Barr virus, and influenza virus (CEF). These T-cell defects were associated with a decrease in production of the T-helper type 1-polarizing cytokine interleukin 12p70 and an increase in interleukin 23 (IL-23) production by gp120-treated mDCs. gp120-induced IL-23 upregulated suppressor of cytokine signaling 1 (SOCS1) protein in T cells, which inhibited IFN-γ production and killing of CEF-pulsed monocytes. These effector functions were recovered by silencing SOCS1 in T...

Infectious Disorders - Drug Targets, 2012

Tat is a viral protein secreted from HIV infected cells and extra cellular Tat is suspected to pr... more Tat is a viral protein secreted from HIV infected cells and extra cellular Tat is suspected to prevent destruction of HIV infected cells from cells of the cellular immunity. The effect of anti retroviral therapy (ART) on Tat secretion has never been investigated. In this study, we tested for antibody reactivity against Tat variants representative of the main HIV subtypes in HIV positive patients receiving ART with undetectable viral loads (< 40 copies/mL) over the course of one year with a blood sampling every three months. For each of theses five blood sampling, an average of 50 % of patients had Anti-Tat IgG, it turned out that 86% of patients could recognize Tat at least in one blood sampling during the course of the study. Amazingly, anti-Tat IgG appeared and/or disappeared in 66 % of patients. Only 20% had anti-Tat IgG remaining persistently while 14% were consistently without anti Tat IgG in the five blood sampling. No significant correlation was found between anti-Tat IgG and CD4+ T cell, CD8+ T cell and B cell counts revealing the incapacity of these anti Tat IgG to neutralize extra cellular Tat. Interestingly the absence and then the appearance of anti-Tat IgG in patients suggest the presence of HIV infected cells in the blood that may constitute a significant reservoir of HIV infected cells. As a conclusion antiretroviral therapy does not block the secretion of Tat and may explain why HIV infected cells can survive in spite of an effective ART treatment.

The Pediatric Infectious Disease Journal, 2014

Background-CD4+ T-lymphocyte (CD4) counts and HIV plasma RNA concentration (RNA) are two key HIV ... more Background-CD4+ T-lymphocyte (CD4) counts and HIV plasma RNA concentration (RNA) are two key HIV disease markers. The complex interplay between virus and host genetics may contribute to differences in viral set point and CD4 status. Determining the effects of host genetic variation on HIV disease markers is often complicated by the use of antiretroviral therapy. In this study, the association between genetic variants and baseline HIV RNA and CD4 counts was examined in a large cohort of antiretroviral naïve children. Methods-Specimens from 1053 HIV-infected children were screened for single nucleotide polymorphisms (SNPs) in 78 regions from 17 genes. Linear regression with a robust variance estimator was used to test the association between genetic markers with HIV RNA and CD4count, controlling for age, race/ethnicity and study. False discovery rate (FDR) controlling was used to adjust for multiple testing. Results-The study population was 60% black, 26% Hispanic and 13% white; median age 2.35 years; 55% female. Baseline median CD4 count was 780/mm 3 ; median log10 HIV RNA was 5.17 copies/mL. For analyses of the associations of genetic makers with baseline CD4+, 6 HLA and 4 additional markers exhibited p-values <0.05, but none met the criteria for statistical significance with FDR controlled at 0.05. For baseline HIV RNA, HLA DRB1*15, DRB1*10, B-27/57, B-14, Cw-8, B57 were statistically significant with FDR controlled at 0.05. Conclusions-These results provide strong evidence that HLA DRB1*15, DRB1*10, B-27/57, B-14, Cw-8, B57 are associated with HIV RNA, and play a role in HIV pathogenesis in infected children. Keywords HIV; host genetics; single nucleotide polymorphism; false discovery rate CD4+ T-lymphocyte cell (CD4) count and HIV plasma RNA concentration (RNA) are the two most commonly used prognostic markers of disease status and clinical progression of

Pediatric Infectious Disease Journal, 2013

Background-Vitamin D deficiency is common in HIV infection and has been associated with advanced ... more Background-Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children. Methods-The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by RT-PCR in HIV-infected children who participated in the PACTG P152 and P300 protocols which pre-dated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease endpoint (≥2 OI's, weight-growth failure) or death, which constituted the progression-free-survival. Analyses were performed for age >2 years and ≤2 years separately adjusting for race and treatment effect. Results-Of the 998 children evaluated, 139 experienced HIV disease progression. For children >2 years, rapid disease progression was associated with the DHCR7 G allele compared to the T allele

Pediatric Infectious Disease Journal, 2014

Background-Contemporary trends in hospitalization patterns among perinatally HIV-infected (PHIV) ... more Background-Contemporary trends in hospitalization patterns among perinatally HIV-infected (PHIV) patients are unknown. We describe rates and reasons for hospitalizations stratified by age group during 2003-2010 within a large cohort of PHIV patients. Methods-579 PHIV patients engaged in care at 6 geographically-diverse pediatric HIV centers affiliated through the HIV Research Network were included. Modified Clinical Classification Software assigned primary ICD-9 codes into diagnostic categories. Analysis was performed using negative binomial regression with generalized estimating equations. Results-There were 699 all-cause hospitalizations. The overall rate for the full cohort was 19.9 / 100 person years, and overall rates for 0-4, 5-16, and 17-24 year-olds were 25.1, 14.7, and 34.2 / 100 person years, respectively. Declines were seen in unadjusted all-cause rates for the whole group (incidence rate ratio per year, 0.93 [0.87, 0.99]) and for 5-16 (0.87 [0.76, 0.99]) and 17-24 year-olds (0.87 [0.80, 0.95]). After adjustment for CD4, HIV-1 RNA, and demographics, rates were no longer declining. Non-AIDS-defining infections and AIDS-defining illnesses together caused 349 (50%) admissions. Declines in these categories drove the overall declines in unadjusted rates. No increases over time were seen for cardiovascular, renal, or any other diagnostic categories. Conclusions-While the declines in hospitalizations are reassuring, continued efforts are needed to address the persistently high infectious and non-infectious morbidity among PHIV patients. Innovative strategies may be most critical for 17-24 year-olds. Lack of increases in

Pediatric Infectious Disease Journal, 2010

The Journal of Infectious Diseases, 2004

Background. Adolescents represent the fastest growing demographic group of new human immunodefici... more Background. Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. Methods. We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. Results. Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. Conclusions. Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication. The use of highly active antiretroviral therapy (HAART) has led to the sustained suppression of viral replication in HIV-infected adults [1-4] and children [5, 6]. Despite available data on adults and perinatally infected

The Journal of Infectious Diseases, 2000

The Journal of Infectious Diseases, 1998

Data from 1330 human immunodeficiency virus type 1 (HIV-1)-infected patients enrolled in seven an... more Data from 1330 human immunodeficiency virus type 1 (HIV-1)-infected patients enrolled in seven antiretroviral treatment trials were analyzed to characterize the clinical benefit of treatmentmediated reductions in plasma HIV-1 RNA levels. The risk of a new AIDS-defining event or death was reduced proportionally to the magnitude of the reduction of the HIV-1 RNA level during the first 6 months of therapy. Pretherapy HIV-1 RNA levels were prognostic independently of ontherapy levels. In addition, the reduction in risk associated with any given reduction of the level of HIV-1 RNA did not vary by pretherapy level. Having either a reduction in HIV-1 RNA level or an increase in CD4 / lymphocyte count, or both, was associated with a delay in clinical disease progression. This indicates that patient prognosis should be assessed using both HIV-1 RNA and CD4 / lymphocyte responses to therapy. High levels of plasma human immunodeficiency virus type of HIV-1 RNA responses to antiretroviral therapy for assessing the prognosis of HIV-1-infected patients. 1 (HIV-1) RNA are strongly predictive of clinical disease progression in HIV-1-infected patients [1-8]. Furthermore, re-A key unanswered question is whether the magnitude of ductions in HIV-1 RNA levels in response to initiation of treatment-mediated reduction in HIV-1 RNA level is proporantiretroviral therapy are associated with a delay in progression tional to the reduction in risk of clinical disease progression. to AIDS and death [5, 6, 9-12]. Despite these findings, im-Such a relationship would imply that larger reductions in HIV-1 portant questions remain concerning the interpretation and use RNA levels confer greater clinical benefit and that antiretroviral therapy should aim for maximal decreases in HIV-1 RNA levels. Alternatively, it could be that there exists a threshold level of reduction beyond which further reduction of the level of

Journal of Clinical Investigation, 2001

Journal of Allergy and Clinical Immunology, 2006