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Questions asked:

Questions asked:. How Nef accomplishes the balance between the conflicting selective forces during a course of HIV-1 infection. Whether CTL responses can impose functional constraints in Nef. a dominant target by CTLs. a pathogenic factor. Nef protein. R PQVPLRPMT Y. R PQVPLRPMT F.

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Questions asked:

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  1. Questions asked: • How Nef accomplishes the balance between the conflicting selective forces during a course of HIV-1 infection. • Whether CTL responses can impose functional constraints in Nef. a dominant target by CTLs a pathogenic factor Nef protein

  2. RPQVPLRPMTY RPQVPLRPMTF TPQVPLRPMTY others Autologous virus sequences in nef database (n=443) This region elicits CTL responses restricted by HLA-B35. T and F mutations are associated with HLA-B35+ patients. early phase (n=14) HLA-B35 negative (n=41) HLA-B35 positive (n=28) RPQVPLRPMTF chronic phase (n=14) TPQVPLRPMTY p<0.001 Interestingly, the TF double mutant is very rare.

  3. TF F T wild The combination of TF mutations may impose functional constraints in Nef Fitness cost?? The TF double mutant can escape from both CTLs. The TF mutations are rarely selected in combination naturally. VY8-CTLs RY11-CTLs

  4. uninfected ｗｔ, RPQVPLRPMTY RPQVPLRPMTF TPQVPLRPMTY HLA class I CD4 n=4 n=4 TPQVPLRPMTF DNef ** ** ** ** p<0.001 The mutant Nefs are impaired in HLA class I down-regulation activity. Primary CD4+ T cells were infected with the following viruses: Gated in live p24 Ag+ subsets

  5. Day 0 3 6 9 12 .... infection to fresh PBMC collection for p24 ELISA PHA activation The double mutant Nef is impaired in enhancement of virus replication HIV-1 replication kinetics in PBMC in vitro The TF double mutant decreased Nef’s activity in enhancement of viral replication, suggesting the selective disadvantage of the variant virus in vivo.

  6. Conclusions • A natural variability in a well-conserved PxxP region in Nef is associated with CTL responses. • CTL escape could have severe consequences on the functionality of Nef, both for its role in immune evasion and intrinsic replicative potential of the virus. • These results highlight CTL immunosurveillance as important modulators of Nef’s biological activity in the infected host during a course of HIV infection.

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