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


CONCLUSIONS
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.
Schindler
Michael
M
Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Wildum
Steffen
S
Casartelli
Nicoletta
N
Doria
Margherita
M
Kirchhoff
Frank
F
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D015754:Genes, nef / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D000944:Antigens, Differentiation, B-Lymphocyte; D000956:Antigens, Viral; D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C045084:invariant chain