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Multi-Faceted Aspects of Acute HIV Infection Concluding remarks

Multi-Faceted Aspects of Acute HIV Infection Concluding remarks. Tony Kelleher Kirby Institute & St Vincent ’ s Centre for Applied Medical Research. Importance of primary HIV infection. Understanding transmission Determinants of outcome and set point Interventions that prevent progression

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Multi-Faceted Aspects of Acute HIV Infection Concluding remarks

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  1. Multi-Faceted Aspects of Acute HIV InfectionConcluding remarks Tony Kelleher Kirby Institute & St Vincent’s Centre for Applied Medical Research

  2. Importance of primary HIV infection • Understanding transmission • Determinants of outcome and set point • Interventions that prevent progression • ART but only if it is continued • Effects of Short course ART modest in preventing progression • Interventions that limit the reservoir • Reduction in size of reservoir is approximately 1 +/- 0.5 log no matter when ART started • Increased relative reduction if commenced very early • Relative limitation of reservoir in certain subsets • Central memory/transitional memory if started very early

  3. Determinants of outcome Host factors (Saulle, et al) • MHC-1 : • HLA-B6802 associated with relative protection • HLA-B57 associated with slower progression, but not in all • relatively weak effect • not previously associated with protection from infection • Additional factors impacting on antigen presentation may impact on propensity for infection • Certain polymorphisms of ERAP 2 plus carriage of B57 confer protection from infection • ? Same effect on progression?

  4. Determinants of outcome Viral/ host factor interactions (Reddy, et al and Cohen, et al) • APOBEC3G: cytosine deaminase,G to A hypermutation • Interaction with Vif degrades APOBEC3G • clade C vif polymorphisms segregate with host APOBEC3G polymorphisms suggesting selection of vif by its effectiveness for inhibition of APOBEC3G • 186 H variant of APOBEC3G was more easily inhibited by natural occurring Vif than is the 186 R variant • Vpu/BST-2: • BST-2: TM protein that inhibits viral release, counteracted by Vpu • Vpu interaction with BST-2 also reduces type 1 IFN response from PDC • Vpu may have an additional role in increasing HIV replication: • increasing viral release and decreased IFN type 1 response

  5. Adaptive responses: ADCC • Wren et al have suggested strong ADCC responses to Vpu are associated with slower progression • Ruiz, et al show ADCC to Env • is present at PHI but increases over time • EC have higher titres of ADCC antibodies • Early initiation of ART blunts increase in response • But no difference in PHI who progressed v those who didn’t • ? Role in slowing progression off therapy • Separately: Madhavi, et al show Env ADCC does segregate with progression off therapy in LTNP c/w rapid progressors, and does decrease with Rx • Will ADCC require boosting to be effective after therapy? • Potential target for therapeutic vaccinations??

  6. Reservoir v activation (Weiss, et al) Complex relationship between immune activation and reservoir • Activation proportional to reservoir as measured by pro-viral DNA in viremic pts • But not in aviremic treated patients • Antigen v homeostatic drivers or Immune activation • differential effects of different types of activation on viral re-activation • Reinfection v expansion of integrated silent reservoir

  7. Points for discussion • Innate v adaptive immunity • Slowing of progression v prevention of infection • What is mechanism of action of something preventing infection that acts post infection? • Do these: Explain eclipse period/ exposure without infection? • How much do these host/viral interactions explain outcomes at PHI such as set point? • Can these inform vaccine development or be used to limit the size of the reservoir? • Effect on viral synapse? Will altering viral transfer improve or blunt the immune response? • Role of ADCC; assessment of ADCC? • Different mechanisms of sustaining the reservoir • relative effects of antigen driven v homeostatic activation and their role in viral activation/ replication: which is the driver?

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