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Association of effective control of HIV-1 with strong ctl selection pressure and a highly mutated nef in a HIV-1-infected patient
Katja Maurer1, Jan Schmökel2, Frank Kirchhoff2, Jennifer Etschel1, Sascha Antoni3, Kathrin Eismann1, Silke Bergmann1, Pia Rauch1, Karin Metzner4
Background: Study of diverse courses of HIV-1 infection in infected couples can provide important clues about the role of host genes and immune effector mechanisms for the control of HIV-1. Here, we report on a female individual with excellent control of HIV-1 who had been infected by her partner who had progressed to AIDS.
Methods: We analyzed viral sequences, CTL, antibodies, CCR5, Apobec3G, HLA and viral replication. Analyses of nef functions were performed by cloning nef genes into an HIV-1 NL4-3 based proviral vector expressing eGFP together with nef. After infection of PBMC by these recombinant reporter viruses, we analyzed various nef functions.
Results: In comparison to viral genes derived from her partner, nef genes derived from the “controller” were highly mutated (21.2% aa divergence and presence of a 5 aa deletion at aa 162-166). Her PBMC could be infected by R5- and X4-tropic HIV-1 strains and a viral isolate showed normal growth characteristics arguing against the presence of a replication deficient virus. The patient showed a good but not an unusual strong antibody response. Analysis of HIV-1-specific CTL revealed a strong CTL response against a variety of epitopes. The detection of CTL targeting epitopes comprising the deleted amino acids in nef strongly indicates that the controllerīs CTL response was responsible for the selection of this deletion. Despite strong sequence divergence, functional analyses of nef alleles derived from the two subjects showed comparable results except for a lower upregulation of the HLA class II invariant chain (Ii,CD74) by nef alleles derived from the controller.
Conclusion: A strong CTL response presumably contributes to the excellent viral control in this individual. An attenuated upregulation of the HLA II invariant chain (CD74) indicates an important immune evasive role of the nef mediated inhibition of HLA class II presentation.
Datei SOEDAK_09_OSC1.pdf