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Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease.

ABSTRACT: HIV infection results in depletion and dysfunction of naïve CD4(+) T cells. The mechanisms underlying these deficiencies are not understood. We investigated the frequencies of CD4(+) naïve subsets in HIV disease as defined by expression of CD25 and/or FoxP3 and the relationship of these frequencies to naïve T cell proliferation function. We observed increased proportions of CD25(+)FoxP3(+) and CD25(+)FoxP3(-) cells and decreased proportions of CD25(-)FoxP3(-) cells within the naïve CD4(+) cell compartment from HIV-infected persons compared with findings in healthy donors. These perturbations were related to higher plasma HIV RNA levels but not with higher immune activation, as measured by the proportions of CD38(+) memory CD4(+) T cells. Naïve T cell proliferation responses to mitogen stimulation were inversely related to the frequencies and absolute numbers of FoxP3(+) naïve T cells. MDA, a marker of oxidative stress, and sCD14, a marker of monocyte activation and a surrogate for microbial translocation, were increased in serum samples from HIV(+) donors; however, neither marker was related to naïve T cell function in HIV(+) donors. These observations suggest that alterations in naïve T cell subset frequencies could contribute to naïve T cell dysfunction in HIV disease, but these alterations are not necessarily the result of chronic immune activation.

SUBMITTER: Rodriguez B

PROVIDER: S-EPMC3157904 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease.

Rodriguez Benigno B Bazdar Douglas A DA Funderburg Nicholas N Asaad Robert R Luciano Angel A AA Yadavalli Gopal G Kalayjian Robert C RC Lederman Michael M MM Sieg Scott F SF

Journal of leukocyte biology 20110607 3

HIV infection results in depletion and dysfunction of naïve CD4(+) T cells. The mechanisms underlying these deficiencies are not understood. We investigated the frequencies of CD4(+) naïve subsets in HIV disease as defined by expression of CD25 and/or FoxP3 and the relationship of these frequencies to naïve T cell proliferation function. We observed increased proportions of CD25(+)FoxP3(+) and CD25(+)FoxP3(-) cells and decreased proportions of CD25(-)FoxP3(-) cells within the naïve CD4(+) cell c ...[more]

PMID: 21653240

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Project description:BackgroundDuring antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear.MethodsHIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA >200 copies/mL at ART initiation and achieved a VL <50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL > 200 copies/mL or 2 VL > 50 copies/mL) while accounting for frequency of VL measurements.ResultsBetween 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3-4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P < .001), female gender (P = .04), lower baseline VL (P < .001), baseline CD4+ >500 vs <350/mm3 (P < .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio <0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P < .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P < .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed.ConclusionsVL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

Project description:Abstract Background HIV-1 set-point viral load (SPVL) is predictive of disease progression and shows variability across HIV-1-positive (HIV+) persons. Various factors may influence SPVL including viral features, environmental exposure and host genetics. To identify single nucleotide polymorphisms (SNPs) associated with SPVL, we performed a genome-wide association study (GWAS) on a subset of participants from the Strategic Timing of AntiRetroviral Treatment (START) study covering a demographically diverse population. Methods. Consenting participants were antiretroviral therapy (ART)-naïve and SPVL was taken as log10(HIV RNA) at study entry. Genotypic data were generated on a custom content Affymetrix Axiom SNP array covering 770,558 probes. The Ensembl Gene database, assembly GRCh37.p13, was used for annotation. Principal component analysis (PCA) was used to identify population structures, and analysis of variance (ANOVA) was performed to detect associations between SNPs and SPVL. SNPs with zero variance or minor allele frequency (MAF) ?0.05 were removed. Results. Among the 2,544 participants, PCA showed distinct population structures with strong separation between black (n = 578) and nonblack (n = 1,966) participants, Figure 1. ANOVA was performed independently on both subsets. Two SNPs located in the Major Histocompatibility Complex (MHC) class I region of chromosome six reached genome-wide significance (P < 5 × 10–8) in the non-black population: rs4418214 (P = 1.74 × 10-10), and rs57989216 (P = 3.96 × 10–8), Figure 2. Two additional SNPs, rs9264942 (P = 5.99 × 10–8) and rs7356880 (P = 9.69 × 10–8), in the same region approached significance. The minor alleles of all four SNPs were associated with lower SPVL, Figure 3. While no SNPs reached genome-wide significance in the black group, we observed similar trends toward lower SPVL for both rs4418214 and rs57989216. Conclusion. In this study we confirm the association of a previously reported SNP (rs4418214) and identify a novel candidate SNP (rs57989216) associated with lower SPVL in a population of nonblack, ART-naïve HIV+ persons. Current findings suggest that the effects of these SNPs are consistent across race groups, but further studies are required to confirm this. Our results support previous findings that variation in the MHC class I region is a major host determinant of HIV-1 control. Disclosures D. D. Murray, Centre of Excellence for Health, Immunity and Infectious diseases (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark: Employee, Salary. J. M. Molina, Gilead: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. ViiV: Scientific Advisor, Consulting fee. Teva: Scientific Advisor, Consulting fee.

Project description:BackgroundInfection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment.MethodsWe analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure.ResultsWe confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-value<2.0x10-5) and Shannon entropy at AA positions which in our association analysis explained 13% of the variance in VL. Finally, equivalent analysis based on variation in HIV consensus sequences explained only 2% of VL variance.ConclusionsOur results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes.Trial registrationSamples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site.

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Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease.

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Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease.

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