1. Multi-Faceted Aspects of Acute HIV Infection Concluding 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?