TOWARD DURABLE CONTROL OF HIV-1 WITH eCD4-Ig

eCD4-Ig is an exceptionally broad HIV-1 entry inhibitor that uniquely neutralizes all of the 270 HIV-1, HIV-2 and SIV isolates it has been tested against, in every case with IC₈₀ values < 10 µg/ml.  eCD4-Ig’s breadth and potency derives from the fact that it closely and simultaneously mimics the HIV-1 receptor CD4 and the HIV-1 coreceptor.  Consistent with this breadth, eCD4-Ig is much harder to escape than broadly neutralizing antibodies (bNAbs).  To date full escape has not been observed either in cell culture or rhesus macaques and viruses which partially escape eCD4-Ig in both cases pay clear fitness costs.  Adeno-associated virus (AAV)-expressed eCD4-Ig functions as an effective vaccine alternative, and protects rhesus macaques from repeated high-dose viral challenges with both SHIV-AD8 and SIVmac239.  Unlike bNAbs and other multispecific antibody-like inhibitors, eCD4-Ig markedly improves the endogenous ADCC activity of patient sera.  It does so by altering the conformation of HIV-1 Env, allowing otherwise dormant V3 and CD4i antibodies to bind Env. To determine whether eCD4-Ig could suppress an established infection, six SHIV-AD8-infected rhesus macaques were placed on combined anti-retroviral therapy (ART) 12 weeks after infection  and inoculated with AAV-eCD4-Ig 42 to 50 weeks post-infection.  ART was subsequently lifted and viral loads and eCD4-Ig concentrations where monitored for now two years. We observed that relatively low concentrations of AAV-expressed eCD4-Ig (3-19 µg/ml) prevent viral rebound of an established SHIV-AD8 infection after ART cessation all six macaques, albeit with sporadic viral ‘blips observed in most animals. Macaques “functionally cured” in this manner could provide an ideal platform to monitor the impact of latency-reversing agents on the reservoir of latently infected cells, and to determine if an entry inhibitor with potent ADCC activity can itself change the rate of reservoir decay.  Stable HIV-1 remissions may also be appealing and useful to humans, for example limiting transmission from individuals who cannot or will not use conventional ART, enabling long-term drug holidays, and providing a backstop for an imperfect sterilizing cure.  Efforts to increase the robustness and consistency of these functional cures will be described.