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Intersubtype differences in the effect of a rare p24 Gag mutation on viral replicative fitness Denis Chopera.

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Presentation on theme: "Intersubtype differences in the effect of a rare p24 Gag mutation on viral replicative fitness Denis Chopera."— Presentation transcript:

1 Intersubtype differences in the effect of a rare p24 Gag mutation on viral replicative fitness Denis Chopera

2 Background Certain immune-driven mutations that occur in conserved regions of the HIV-1proteome often affect viral replication [Brockman et. al., 2010; Crawford et. al., 2007; Miura et. al., 2009] Rare mutations occurring in p24 Gag were identified in elite controllers in subtype B infections and these have a severe fitness cost to viral replication [Miura et. al., 2009] The extent to which these mutations affect viral fitness in other HIV-1 subtypes has not been explored.

3 Study Objectives This study examined the impact of a rare Gag mutation, M250I, on subtype B and C viral replicative fitness Rationale: -M250I is one of the mutations identified in elite controllers in subtype B [Miura et. al., 2009] -The mutation is negatively associated with a common HLA-B*57 escape mutation, T242N [Martinez-Picado et. al., 2006; Chopera et. al., 2011]

4 Distribution of M250I by cohort and HLA in subtype B -M250I associated with HLA-B58 supertype and is enriched in elite controllers in subtype B infections

5 M250I and subtype B replication -M250I impairs viral replication in vitro

6 Distribution of M250I by cohort in subtype C -M250I more common in subtype C viruses

7 Subtype C replication capacity -Impairs viral replication in site-directed mutants but not in patient-derived isolates

8 Why is the M250I mutation more common in subtype C infections and why is it not associated with a fitness cost in plasma-derived viruses????? Secondary mutations have been shown to fully or partially restore viral fitness incurred by CTL escape mutations [Brockman et. al., 2007; Crawford et. al., 2007; Schneidewind et. al., 2007] We applied phylogentically-corrected methods to detect amino acids that co-vary with the M250I mutation

9 Codon 250Covarying codonAssociationTTTFFTFFTotalp-valueq-value 250M252GNegative553173474137.4E-09 8.0E-06 250M260DPositive2641084374131.9E-08 8.0E-06 250M252SPositive2201532384132.7E-07 7.0E-05 250M247MNegative03724364122.5E-05 5.0E-03 250M256VPositive1921803384133.3E-05 5.0E-03 250M207DPositive38334041413 2.2E-043.0E-02 250M260ENegative107265374413 7.5E-048.0E-02 250I252GPositive336553184121.4E-08 8.0E-06 250I260DNegative4362641104141.4E-07 4.0E-05 250I252SNegative2372201544135.4E-07 1.0E-04 250I256VNegative3371921814135.0E-05 7.0E-03 250I247MPositive43503744135.9E-05 8.0E-03 250I207DNegative03938335412 3.1E-043.0E-02 250I260EPositive364109265414 8.2E-048.0E-02 TT - Number of sequences with both codon 250 residue and covarying residue TF - Number of sequences with codon 250 residue but without covarying residue FT - Number of sequences without codon 250 residue but with covarying residue FF - Number of sequences with neither codon 250 residue nor covarying residue Covariation between codon 250 and other Gag sites in the chronic subtype C cohort

10 M250I compensation in subtype C and B viruses -There is compensation of M250I mutation in subtype C but not subtype B viruses

11 Effect of M250I mutation on p24 helix-6 -M250I destabilizes capsid helix 6 in subtype B viruses

12 Summary In subtype B infections, the M250I mutation is very rare and enriched in elite controllers expressing HLA- B58 supertype The mutation is associated with a reduction in viral replication in subtype B viruses M250I is not associated with a fitness cost in patient- derived (subtype C) isolates In subtype C, the associated mutations, S252G and D260E partially restore viral replication M250I destabilizes helix 6 of the capsid and this effect is more pronounced in subtype B

13 Conclusion Understanding the selection mechanism for the M250I mutation may be useful for HIV vaccine immunogen design Vaccine designing strategies need to take into consideration the inter-subtype differences in the specific mutations selected by under immune pressure and their relative impact on viral fitness

14 Acknowledgements Dr. Zabrina Brumme Dr. Mark Brockman Eric Martin Laura Cotton Dr. Carolyn Williamson Dr. Clive Gray Dr. Zenda Woodman Dr. Darren Martin Dr. Nobubelo Ngandu Dr. Roman Ntale Dr. Salim Abdool-Karim Dr. Koleka Mlisana CAPRISA 002 Study Team Dr. Jonathan Carlson Dr. Thumbi Ndung’u Dr. Jaclyn Mann (Wright) Dr. Richard Harrigan Dr. Bruce Walker Dr. Toshiyuki Miura Dr. Florencia Pereyra

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