Dataset Information

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

ACCESS DATA

Publications

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

Similar Datasets

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:BACKGROUND:The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS:Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS:These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure