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Title: Detection and genetic characterisation of HIV-1 variants infecting different subsets of CD4+ and CD8+ T lymphocytes in vivo
Author: McBreen, Sarah
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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To investigate the mechanism and functional significance of infection of CD8 lymphocytes by human immunodeficiency virus type 1 (HIV-1) in vivo, frequencies of infection and genetic relationships between HIV-1 variants infecting native (CD45RA+) and memory (CD45RO+) CD4 and CD8 lymphocytes was carried out. CD4 and CD8 lymphocytes were purified from peripheral blood mononuclear cells from 16 study subjects by negative selection, followed by positive selection of each of the two subsets with anit-CD45RA and -RO monoclonal antibody-coated beads. The contribution to total proviral load by the naive and memory subsets was estimated by quantitative PCR combined with measurement of their frequency in total T lymphocytes. In this analysis we found that HIV preferentially infects the naive subset of CD8+ lymphocytes along with the naive and memory populations of CD4+ cells. Sequence comparisons of the V1/V2 and V3 region of the envelope gene was also carried out on the naive and memory subsets of CD4 and CD8 cells. Variants infecting CD8 lymphocytes were partially or completely genetically distinct in the V3 region from those recovered from CD4 lymphocytes, and showed a greater degree of compartmentalisation than observed between naive and memory subsets of CD4 lymphocytes. A preferential distribution of syncytium-inducing, CXCR4-dependnet variants was also observed within CD4 lymphocytes. Even more marked sequence differences were observed upon sequence comparison of the V1/V2 hypervariable region, with some evidence for recombination between V1/V2 and V3 regions. Population differences may have originated through different times of infection rather than necessarily indicating a difference in their biological properties. In this study we provide evidence for the widespread infection of CD4 and CD8 naive and memory cell populations within the peripheral blood of HIV seropositive individuals, indicating that HIV has a broader tropism for cell types in vivo than described previously. The preferential distribution of HIV-1 in naive CD8 lymphocytes suggests that infection occurred early in T lymphocyte ontogeny, such as during maturation in the thymus. Destruction of cells destined to become CD8 lymphocytes may be a major factor in the decline of CD8 lymphocytes frequencies and function on disease progression, and contribute directly to the observed immunodeficiency in AIDS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available