Assessment of Thymic Activity in Human Immunodeficiency Virus-Negative and -Positive Adolescents by Real-Time PCR Quantitation of T-Cell Receptor Rearrangement Excision Circles

Pham, Thao Thi Ngoc; Belzer, Marvin; Church, Joseph A.; Kitchen, Christina M. R.; Wilson, Craig M.; Douglas, Steven D.; Geng, Yongzhi; Silva, Mónica; Mitchell, Richard M.; Krogstad, Paul

doi:10.1128/cdli.10.2.323-328.2003

Cited by 16 publications

(13 citation statements)

References 39 publications

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“…TREC concentration was assessed using a previously described real-time PCR protocol (39). Briefly, cell lysates from PBMC and sorted CD4 ϩ T cell subsets were created by incubating each sample with 100 g/ml proteinase K (Boehringer Ingelheim) for 1 h at 56°C.…”

Section: Trec Concentration Measurementmentioning

confidence: 99%

Homeostasis of the Naive CD4+ T Cell Compartment during Aging

Kilpatrick

Rickabaugh

Hultin

et al. 2008

The Journal of Immunology

194

195

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Despite thymic involution, the number of naive CD4+ T cells diminishes slowly during aging, suggesting considerable peripheral homeostatic expansion of these cells. To investigate the mechanisms behind, and consequences of, naive CD4+ T cell homeostasis, we evaluated the age-dependent dynamics of the naive CD4+ T cell subsets CD45RA+CD31+ and CD45RA+CD31−. Using both a cross-sectional and longitudinal study design, we measured the relative proportion of both subsets in individuals ranging from 22 to 73 years of age and quantified TCR excision circle content within those subsets as an indicator of proliferative history. Our findings demonstrate that waning thymic output results in a decrease in CD45RA+CD31+ naive CD4+ T cells over time, although we noted considerable individual variability in the kinetics of this change. In contrast, there was no significant decline in the CD45RA+CD31− naive CD4+ T cell subset due to extensive peripheral proliferation. Our longitudinal data are the first to demonstrate that the CD45RA+CD31+CD4+ subset also undergoes some in vivo proliferation without immediate loss of CD31, resulting in an accumulation of CD45RA+CD31+ proliferative offspring. Aging was associated with telomere shortening within both subsets, raising the possibility that accumulation of proliferative offspring contributes to senescence of the naive CD4+ T cell compartment in the elderly. In contrast, we observed retention of clonal TCR diversity despite peripheral expansion, although this analysis did not include individuals over 65 years of age. Our results provide insight into naive CD4+ T cell homeostasis during aging that can be used to better understand the mechanisms that may contribute to immunosenescence within this compartment.

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Section: Trec Concentration Measurementmentioning

confidence: 99%

Homeostasis of the Naive CD4+ T Cell Compartment during Aging

Kilpatrick

Rickabaugh

Hultin

et al. 2008

The Journal of Immunology

194

195

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“…18 Eight of these 13 were subsequently enrolled in a study of the impact of HIV replication on thymopoiesis 19 and followed into early adulthood (19.2 to 21.4 years, median 21.1 years). These studies were approved by Institutional Review Boards of CHLA and the University of California, Los Angeles (UCLA) and informed consent was obtained from study participants or their parent or guardians.…”

Section: Study Subjectsmentioning

confidence: 99%

Functional Analysis of HIV Type 1 Nef Gene Variants from Adolescent and Adult Survivors of Perinatal Infection

Zuo

Suen

Wong

et al. 2012

AIDS Research and Human Retroviruses

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Throughout the world, infants and children with HIV-1 infection are increasingly surviving into adolescence and adulthood. As HIV Nef is an important determinant of the pathogenic potential of the virus, we examined nef alleles in a cohort of extreme long-term survivors of HIV infection (average age of 16.6 years) to determine if Nef defects might have contributed to patient survival. HIV nef gene sequences were amplified for phylogenetic analysis from 15 adolescents and adults infected by mother-to-child transmission (n = 10) or by blood transfusion (n = 5). Functional analysis was performed by inserting patient-derived nef sequences into an HIV-derived vector that permits simultaneous evaluation of the impact of the Nef protein on MHC-I and CD4 cell surface expression. We found evidence of extensive nef gene diversity, including changes in known functional domains involved in the downregulation of cell surface MHC-I and CD4. Only 3 of 15 individuals (20%) had nef alleles with a loss of the ability to downregulate either CD4 or MHC-I. Survival into adulthood with HIV infection acquired in infancy is not uniformly linked to loss of function in nef. The Nef protein remains a potential target for immunization or pharmacologic intervention.

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“…Proviral sequences were derived from cryopreserved PBMC by direct PCR previously described (17). Briefly, simple lysates of PBMC DNA prepared were used as the template for limiting dilution nested PCR amplification (23). Limiting dilution was determined by serial twofold dilutions to the point at which less than 50% of six PCR mixtures generated a product.…”

Section: Mapping Of Cd8mentioning

confidence: 99%

Genetic and Stochastic Influences on the Interaction of Human Immunodeficiency Virus Type 1 and Cytotoxic T Lymphocytes in Identical Twins

Yang

Church

Kitchen

et al. 2005

J Virol

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Human immunodeficiency virus type 1 (HIV-1) evolves in vivo under selective pressure from CD8؉ Tlymphocyte (CTL) responses, which are in turn determined by host and viral genetic factors, such as restricting major histocompatibility complex molecules and the available viral epitope sequences. However, CTL are derived stochastically through the random gene rearrangements to produce T-cell receptors (TCR), and the relative impact of genetic versus stochastic processes on CTL targeting of HIV and immune-driven viral evolution is unclear. Here we evaluate identical twins infected with HIV-1 as neonates from a common blood transfusion, with subsequently similar environmental exposures, thereby allowing controlled comparisons of CTL targeting and viral evolution. Seventeen years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable.

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Assessment of Thymic Activity in Human Immunodeficiency Virus-Negative and -Positive Adolescents by Real-Time PCR Quantitation of T-Cell Receptor Rearrangement Excision Circles

Cited by 16 publications

References 39 publications

Homeostasis of the Naive CD4+ T Cell Compartment during Aging

Homeostasis of the Naive CD4+ T Cell Compartment during Aging

Functional Analysis of HIV Type 1 Nef Gene Variants from Adolescent and Adult Survivors of Perinatal Infection

Genetic and Stochastic Influences on the Interaction of Human Immunodeficiency Virus Type 1 and Cytotoxic T Lymphocytes in Identical Twins

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