AEGiS-05CROI: Antiretroviral drug-mediated suppression of HIV-1 results in loss of CD8+ T cell receptor (TCR) skewing and reduced frequency of epitope-specific CD8+ Cells.

5th Conference on Retroviruses and Opportunistic Infections


Chicago, IL - February 1-5, 1998



Antiretroviral drug-mediated suppression of HIV-1 results in loss of CD8+ T cell receptor (TCR) skewing and reduced frequency of epitope-specific CD8+ Cells.

Conf Retroviruses Opportunistic Infect 1998 Feb 1-5; 5th:82 (abstract no. 19)

Gray CM, Schapiro JM, Altman J, Lawrence J, Crompton M, Merigan TC; Stanford University, Stanford, CA.

Aim: to determine whether suppression of viral replication by highly active antiretroviral therapy (HAART) causes alterations to the TCR repertoire and antigenicity of circulating CD8+ cells.

METHODS: A confined TCR repertoire was evaluated over six months in ten asymptomatic patients receiving triple drug HAART, consisting of indinavir, zidovudine and 3TC. TCR expression by CD8+ cells was assessed by flow cytometry using a panel of FITC-conjugated monoclonal antibodies specific to eight Vbeta and two Valpha regions. The frequency of epitope-specific CD8+ cells was assessed using a PE-conjugated soluble tetrameric HLA-A*0201 complex. Tetramers expressing an epitope in either gag (SLYNTAVTL) or pol (ILKEPVHGV) were used to assess the frequency of antigen-specific CD8+ cells in patients receiving quadruple drug HAART, consisting of new formulation saquinavir, nelfinavir, d4T and 3TC.

RESULTS: relative to seronegative controls, 5/10 patients prior to triple drug HAART showed significant skewing towards Vbeta12, ranging from 13.3-49.6% CD8+ cells. One of the five had skewing to Vbeta8 (30%), 4 had a skew to Vbeta6.7 (5.8-15.1%) and 3 skewed to Vbeta5.1 (10-18%). Overall 6/10 patients showed increased usage of Vbeta6.7 prior to therapy. After 8 weeks, there was a specific loss of Vbeta12 usage (P less than 0.005) accompanied by an overall loss (P less than 0.05) of TCR skewing as assessed by permutated data matrix analysis. These changes were accompanied by a mean plasma viral load drop of 1.94 plus or minus 0.68 log10 RNA copies/ml. After 24 weeks, some skewing returned in parallel with elevated viral loads, where increased Vbeta6.7 TCR usage was observed in 7/10 patients. However, Vbeta12 TCR CD8+ expression remained significantly reduced. Changes in the frequency of gag- and pol-specific CD8+ cells in a representative patient receiving quadruple drug HAART is shown: (Table: see text)

CONCLUSION: suppression of viral replication by HAART results in a broadened CD8+ TCR repertoire and a reduced frequency of HIV-1 epitope specific CD8+ cells. These data suggest that replicating virus is required to maintain high frequencies of antigen-specific cells.

Keywords: AEGIS, HIV-1, Receptors, Antigen, T-Cell, Antigens, CD8, Antiretroviral Therapy, Highly Active, Viral Load, Epitopes, Anti-HIV Agents, Lamivudine, Virus Replication, Zidovudine, Indinavir, HIV Protease Inhibitors, HIV-1 Reverse Transcriptase, Reverse Transcriptase Inhibitors, Human, virology, AIDS

1998-02-01
19

Copyright © 1998 - Foundation for Retrovirology and Human Health (IAS). Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed from National Library of Medicine.