Project Summary/Abstract: The main goal of our proposed studies is to evaluate select SIVs for their potential for human transmission using a humanized mouse (hu-mouse) human surrogate animal model. Cross-species transmission events give rise to several deadly human pathogens including HIV-1 and HIV-2 and more recently SARS-CoV-2. While only four HIVs have established themselves in human populations (HIV-1 group M, HIV-1 group O, HIV -2 groups A and B) outbreaks, there were many other lesser ones, namely HIV-1 group P and N and HIV-2 groups C through I, indicating that SIV transmissions to humans are not infrequent events. More than 40 SIVs exist in the wild in non-human primates (NHP) in West and Central Africa and human encroachment into their habitat continues to accelerate, suggesting that potential for the emergence of new human pathogens still exists. Thus, we need to be vigilant and conduct viral surveillance. In this context, animal models that can permit testing of SIV cross- species transmission and evolution are needed. For this purpose, the new generation hu-mice that harbor a transplanted human immune system appear to be highly suitable. In work centered on SIV progenitor viral evolution into HIVs, we and others found that hu-mice are susceptible to SIV-chimpanzee (SIVcpz) the progenitor of HIV-1 and SIV-sooty mangabey (SIVsm) the progenitor of HIV-2. More recently, we discovered that hu-mice are also permissive to macaque-derived SIVmac251, a widely used virus in NHP studies in the context of HIV research. However, thus far no previous studies examined the human infection potential of more primitive SIVs in the wild. Here we will evaluate two SIV strains, namely SIVrcm from red capped mangabeys and SIVmnd2 from mandrils, viruses from two distinct NHP species. These were previously studied in their native hosts wherein they display high viral loads but are non-pathogenic. These two viruses are genetically linked to SIVcpz which is the progenitor for HIV-1. While a full comprehensive study of these in vivo will be a complex undertaking, here in this R21 grant of a limited budget and scope, we propose to start with the following simpler initial goals. Aim 1: Investigate the potential for zoonotic transmission and sustained human infection by select SIVs, SIVrcm and SIVmnd2 using a humanized mouse model. Aim 2: Characterize key pathogenic attributes of the human adapted viruses for cell tropism, helper CD4 T cell loss and capacity for sexual transmission. Knowledge gained from here will shed light on the initial steps in cross-species transmission.