Gag Cytotoxic T Lymphocyte Escape Mutations Can Increase Sensitivity of HIV-1 to Human TRIM5α, Linking Intrinsic and Acquired Immunity

Author:

Battivelli Emilie12,Migraine Julie12,Lecossier Denise12,Yeni Patrick3,Clavel François12,Hance Allan J.123

Affiliation:

1. INSERM U941, Paris 75010, France

2. Institut Universitaire d'Hématologie, Université Paris Diderot, Hôpital Saint-Louis, Paris 75010, France

3. Service des Maladies Infectieuses et Tropicales, Assistance Publique—Hôpitaux de Paris, Hôpital Bichat—Claude Bernard, Paris 75018, France

Abstract

ABSTRACT Although laboratory-adapted HIV-1 strains are largely resistant to the human restriction factor TRIM5α (hTRIM5α), we have recently shown that some viruses carrying capsid (CA) sequences from clinical isolates can be more sensitive to this restriction factor. In this study we evaluated the contribution to this phenotype of CA mutations known to be associated with escape from cytotoxic T lymphocyte (CTL) responses. Recombinant viruses carrying HIV-1 CA sequences from NL4-3 and three different clinical isolates were prepared, along with variants in which mutations associated with CTL resistance were modified by site-directed mutagenesis, and the infectivities of these viruses in target cells expressing hTRIM5α and cells in which TRIM5α activity had been inhibited by overexpression of TRIM5γ were compared. For both hTRIM5α-sensitive viruses studied, CTL-associated mutations were found to be responsible for this phenotype. Both CTL resistance mutations occurring within HLA-restricted CA epitopes and compensatory mutations occurring outside CTL epitopes influenced hTRIM5α sensitivity, and mutations associated with CTL resistance selected in prior hosts can contribute to this effect. The impact of CTL resistance mutations on hTRIM5α sensitivity was context dependent, because mutations shown to be responsible for the TRIM5α-sensitive phenotype in viruses from one patient could have little or no impact on this parameter when introduced into another virus. No fixed relationship between changes in hTRIM5α sensitivity and infectivity was discernible in our studies. Taken together, these findings suggest that CTL mutations may influence HIV-1 replication by modifying both viral infectivity and sensitivity to TRIM5α.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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