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Thesis Fransje Koning

On 26 November 2004 Fransje Koning will defend her thesis "Determinants of host HIV-1 suspectibility and R5 HIV-1 evolution" at the University of Amsterdam.

Promotores: Prof. dr. F. Miedema and prof.dr. J. Schuitemaker (Sanquin Research at CLB, Amsterdam)

The research for this thesis was performed at the Department of Clinical Viro-Immunology and the Landsteiner Laboratory of the Amsterdam Medical Center, University of Amsterdam.
The studies werd financially supported by the Netherlands Organization for Scientific Research (NWO) and the Dutch AIDS fund.

Summary
This thesis contains research on sensitivity of HIV-1 to R5 inhibitors and on features that may influence HIV-1 resistance in high-risk seronegative (HRSN) individuals. We detected the emergence of HIV-1 variants with a decreased sensitivity to inhibition by RANTES in individuals who progress to AIDS in the presence of only R5 variants. Phylogenetic analysis of R5 HIV-1 gp120 showed a rapid accumulation of mutations in individuals with rapid disease progression in the presence of only R5 variants and a positive selection on the variable regions of gp120 in R5 variants from individuals heterozygous for the CCR5-D32 genotype.
Research on exposed but persistently HIV-seronegative individuals may provide clues about features that influence host HIV-1 susceptibility. ELIspot analysis revealed low frequencies of HIV-1-specific cytotoxic T cells (CTL) in both HRSN individuals and pre-seroconversion controls, indicating that the presence of HIV-1-specific CTL may signify exposure to the virus rather than protection from infection. We detected extraordinary low levels of HIV-1 DNA in homosexual men with high-risk sexual behaviour in the absence of seroconversion. Finally, the detection of reduced CD4+ T cell activation, reduced numbers of naïve CD4+ and CD8+ T cells and increased CD8+ T cell activation in HRSN men, suggest a role for immune activation in HIV-1 susceptibility.

Contents

  • Chapter 1
    Introduction

  • Chapter 2
    Biological and molecular aspects of HIV-1 coreceptor usage.
    HIV Sequence Compendium 2002; Edited by: Kuiken C et al. pp. 24-42.
    http://www.hiv.lanl.gov/content/hiv-db/COMPENDIUM/2002/partI/Schuitemaker.pdf

  • Chapter 3
    No selection for CCR5 coreceptor usage during parenteral transmission of macrophagetropic syncytium-inducing HIV-1.
    J Virol 2001; 75:8848-53.

  • Chapter 4
    Decreasing sensitivity to RANTES neutralization of CCR5-using non-synsytium inducing virus variants in the course of HIV-1 infection.
    J Infect Dis 2003; 188:864-72.

  • Chapter 5
    Sensitivity of primary R5 HIV-1 to inhibition by RANTES correlates with sensitivity to small-molecule R5 inhibitors.
    Submitted for publication

  • Chapter 6
    Evolution of R5 gp120 in patients who do not develop X4 variants.
    Manuscript in preparation

  • Chapter 7
    Correlates of resistance to HIV-1 infection in homosexual men with high-risk sexual behaviour
    AIDS 2004; 18:1117-26.

  • Chapter 8
    Low level of CD4+ T cell activation is associated with low susceptibility to HIV-1
    Submitted for publication

  • Chapter 9
    Low levels of HIV-1 DNA in high-risk seronegative men.
    Submitted for publication

  • Chapter 10
    General discussion

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