DESCRIPTION (provided by applicant): We have developed and characterized eCD4-Ig, an exceptionally broad and potent HIV-1 entry inhibitor. eCD4-Ig is a fusion of CD4-Ig - a safe but ineffective therapeutic - with a short CCR5- mimetic sulfopeptide. eCD4-Ig is qualitatively different from CD4-Ig or broadly neutralizing antibodies (bNAbs) because it avidly binds two highly conserved and functionally important receptor-binding regions of the HIV-1 envelope glycoprotein, and only those sites. As a consequence, eCD4-Ig, but not CD4-Ig or bNAbs, neutralized 100% of isolates tested, including both R5- and X4-isolates, and two large panels of antibody-resistant HIV-1, HIV-2 and SIV isolates, all with IC50s < 1.2 µg/ml and IC80s less < 5.2 µg/ml. Moreover, in unpublished data, we show that eCD4-Ig is much harder to escape than CD4-Ig or a well characterized CD4-binding site bNAb, and in fact we have yet to identify isolates fully resistant to eCD4-Ig. Most importantly, and again in contrast to bNAbs, eCD4-Ig could provide long- term protection in vivo. When four rhesus macaques were inoculated intramuscularly with an adeno- associated virus (AAV) vector expressing a rhesus form of eCD4-Ig, these macaques were protected from six infectious and escalating challenges with SHIV-AD8. The last of these challenges, also unpublished, were 8- and 16-times the 50% animal infectious dose of SHIV-AD8, and were administered more than one year after inoculation. Here our primary goal is to understand the strengths and limitations of passively administered and AAV-delivered eCD4-Ig as potential alternatives to current antiretroviral regimens. These studies will also help to understand the risks and improve the safety of AAV-eCD4-Ig, perhaps facilitating its use as an alternative vaccine.