Emergence of cytotoxic T lymphocyte escape mutants following antiretroviral treatment suspension in rhesus macaques infected with SIVmac251.
Structured treatment interruption (STI) of antiretroviral drugs has been proposed as an alternative approach for managing patients infected with HIV-1. While STI is thought to spare drug-related side effects and enhance the HIV-1-specific immune response, the long-lasting clinical benefit of this approach remains uncertain, particularly in patients with long-standing HIV-1 infection. Here, we investigated the basis of unabated virological replication following different STI regimens in rhesus macaques that expressed the MHC class I Mamu-A*01 molecule treated during acute and long-standing infection with SIVmac251. An amino acid change at the anchor residue within the immunodominant Mamu-A*01-restricted Gag(181-189) CM9 epitope (T --> A) in one of six macaques with acute SIVmac251 infection and in three of four macaques with long-standing SIVmac251 infection (T --> A; T --> S; S --> C) was found in the majority of plasma virus. These amino acid changes have been shown to severely decrease binding of the corresponding peptides to the Mamu-A*01 molecule and, in the case of the T --> A change, escape from CTL. In one macaque with long-standing SIVmac251 infection, a mutation emerged that conferred resistance to one of the antiretroviral drugs (PMPA) as well. These results provide insights into the mechanism underlying the limited capacity of repeated interruption of antiretroviral therapy as an approach to restrain viral replication. In addition, these data also suggest that interruption of therapy may be less effective in chronic infection because of preexisting immune escape and that immune escape is a risk of interruption of therapy.
Nacsa
Janos
J
National Cancer Institute, Basic Research Laboratory, 41/D804, Bethesda, Maryland 20892, USA.
Stanton
Jennifer
J
Kunstman
Kevin J
KJ
Tsai
Wen Po
WP
Watkins
David I
DI
Wolinsky
Steven M
SM
Franchini
Genoveffa
G
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000939:Epitopes; D015683:Gene Products, gag / Q000276:immunology; D008253:Macaca mulatta; D009154:Mutation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014766:Viremia / Q000276:immunology
D019380:Anti-HIV Agents; D000939:Epitopes; D015683:Gene Products, gag