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Nef alleles from children with non-progressive HIV-1 infection modulate MHC-II expression more efficiently than those from rapid progressors

Schindler, Michaela; Wildum, Steffena; Casartelli, Nicolettab; Doria, Margheritab; Kirchhoff, Franka

doi: 10.1097/QAD.0b013e32816aa37c
Basic Science: Concise Communication

Background: It has been established that defective nef genes and differences in the Nef-mediated downmodulation of CD4 and MHC-I cell surface expression can be associated with different rates of HIV-1 disease progression.

Objective: To evaluate whether nef alleles derived from perinatally HIV-1-infected children showing no, slow or rapid disease progression differ in their abilities to downmodulate mature MHC-II or to upregulate the invariant chain (Ii) associated with immature MHC-II complexes.

Methods: Nef alleles derived from HIV-1-infected children were cloned into expression vectors and proviral HIV-1 constructs co-expressing Nef and enhanced green fluorescence protein via an internal ribosomal entry site. Nef-mediated modulation of CD4, MHC-I, MHC-II or Ii surface expression was analysed by flow cytometric analysis of Jurkat T cells, monocytic THP-1 cells, CD4 T cells and macrophages transduced with vesicular stomatitis virus G-pseudotyped HIV-1 nef variants or transiently transfected HeLa class II transactivator cells.

Results: Nef alleles derived from HIV-1-infected children with non-progressive infection were significantly more active in the upregulation of Ii and downregulation of MHC-II than those derived from rapid progressors.

Conclusion: Nef alleles particularly active in interfering with MHC-II antigen presentation are more frequently found in perinatally HIV-1-infected non-progressors than rapid progressors. Possibly in the context of an immature host immune system, strongly impaired MHC-II function might contribute to lower levels of immune activation and a decelerated loss of CD4 T cells.

From the aInstitute of Virology, University of Ulm, Ulm, Germany

bDivision of Immunology and Infectious Disease, Children's Hospital ‘Bambino Gesù’, Rome, Italy.

Received 3 October, 2006

Revised 6 March, 2007

Accepted 13 March, 2007

Correspondence to Frank Kirchhoff, Institute of Virology, University of Ulm, Albert-Einstein Allee 11, 89081 Ulm, Germany. Tel: +49 731 50065109; fax: +49 731 50065131; e-mail: frank.kirchhoff@uniklinik-ulm.de

© 2007 Lippincott Williams & Wilkins, Inc.