View All Abstracts for Session 26
136 Why Antigen-Specific CD8 T Lymphocytes Fail to Prevent Progressive Immunodeficiency in HIV-1 Infection
J. Andersson1, K. Lore1, A. Sonnerborg1, L. Perrin2, D. Cooper3, B. Gazzard4,S. Kinloch4, R. Weber5, H. Stellbrink6, C. Tsoukas7, G. Tambussi8, and L. Goh9
Depts. of Inf. Diseases, 1Sweden, 2Geneva, 3Australia, 4London, 5Zurich, 6Hamburg, 7Montreal, 8Milan, and 9GlaxoSmithKline
Background: High frequencies of HIV-1-specific CD8 T cells is linked with viral drop, but this response fails to inhibit HIV replication efficiently leading to eventual immunodeficiency. Identification of defects in the antiviral activity of CD8 T cells is important to contain HIV-1.
Methods: Lymphoid tissue (LT) were collected from different HIV patient cohorts: acute infection (aHI, n = 6), HAART untreated, chronics (uCI, n = 7), treated aviremic (tCI, n = 4), AIDS (n = 5), acute Epstein-Barr Virus-infected (aEBV, n = 6); and uninfected controls (uC, n = 6). Expression of costimulatory (Csm) and CTL effector molecules involved in T-cell interactions were quantified at the single cell level by in situ imaging.
Results: Recruitment of interdigitating dendritic cells (DC) expressing CD1a, S-100b, CD83, and DC-sign were detected in LT of both aHI and aEBV (p < 0.02 vs. uC). The Csm CD80 and CD86 were only partially up-regulated in aHI without generating a complete parafollicular network vs. aEBV, despite signs of activation including IL-1alpha/beta/ra, IFN-alpha, IL-12, and CD40 expression. An increased incidence of iDCs and low expressions of CD80 and CD86 were also found in the other HIV-1 cohorts except in AIDS where the frequency of DCs was reduced. A 4- to 9-fold expansion of CD8+ T cells in the LT was observed in both aHI and aEBV vs. uC. Although there was a massive >10-fold increase in the incidence of granzyme A +ve (Gra-A) CD8 precursor CTL in aHI and aEBV, <10% of these cells coexpressed perforin (PER) in aHI vs. parallel increases in aEBV. The PER reduction was further associated with a defect in the migration of Gra-A to the nucleus of p24 Ag expressing cells in aHI.
Conclusions: Low CD80 and CD86 expression may result in poor activation of HIV sp. CD4 T cells leading to inadequate CD8 T cells signalling, causing a defect in PER induction and development of functional CD8 effector CTL (CD28(, CD27(, CD45RO, CCR7+, PER, and Gra high). Early HAART followed by immunisation, may provide an optimal HIV-1 Ag presentation and costimulation on DC for recruitment of naïve CD4 T cells thus restoring final eCTL CD8 T-cell maturation.
Contact Author about this Abstract
