Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. 1 g/ml), and V4 (IC50, 5 g/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant ( 1,000-fold) to antibody neutralization and another fraction (20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens. INTRODUCTION Similarities between simian immunodeficiency virus (SIV) contamination of rhesus macaques and human immunodeficiency virus type 1 (HIV-1) contamination of humans were first recognized in the 1980s, when captive Asian-origin macaques were found to be infected with an immunodeficiency-causing retrovirus originating with African-origin sooty mangabeys (1C6). Whereas SIVsmm viruses cause a nonpathogenic contamination in their natural hosts (7), they produce a pathogenic contamination in macaques, with virologic and clinical outcomes that parallel those of HIV-1 contamination in humans. Like HIV-1, SIVsmm and SIVmac infect CD4+ T cells, utilize CCR5 as a coreceptor, establish high peak and setpoint Halofuginone viremia, and cause generalized immune activation and a profound acute Halofuginone and sustained loss of intestinal CD4+ T cells (3, 8, 9). As in HIV-1 contamination, these events lead to progressive immune deficiency, opportunistic infections, AIDS-defining neoplasms, and death in the majority of infected animals (10). Given these parallels with HIV contamination, the SIV-nonhuman primate (NHP) model has been utilized as an important component of HIV vaccine development efforts. There are many iterations of this NHP Halofuginone model, with options in animal species, challenge viruses, inoculation routes, dosing strategies, and intrinsic host genetic restriction factors. Though there is no single standardized SIV-NHP contamination model, much of the recent work in antibody- and cell-based vaccine design and assessment has been conducted with Indian-origin rhesus macaques challenged with SIVsmm and SIVmac viruses. Two of the most commonly used challenge viruses in the macaque model are the isolates SIVsmE660 and SIVmac251, along with the latter’s derivative clone SIVmac239. SIVsmE660 was originally isolated from a rhesus macaque (Rh660) with a terminal AIDS-defining illness after it had been infected with virus previously passaged through three rhesus macaques. The Rh660 spleen homogenate was then cocultured with human CEMx174 cells and passaged through pigtail macaque peripheral blood mononuclear cells (PBMCs) to obtain the virus challenge stock (9, 11). SIVmac251 was also isolated terminally from SIV-infected macaque spleen cells after the macaque Halofuginone had been infected with virus cocultured with human PBMCs and serially passaged through rhesus PBMC cultures (12). Based on uncorrected mean character differences, the SIVmac251 and SIVsmE660 virus swarms are each approximately 77% Agt identical in amino acid sequence to HIV-2, which originated from a cross-species transmission of SIVsmm from sooty mangabeys to humans, but only 52 to 57% identical to HIV-1 (9, 13C16). Despite these differences in primary amino acid sequence, SIVsmE660, SIVmac251, HIV-2, and HIV-1 are all highly related from an envelope (Env) structure-function perspective (15, 16). SIVsmE660 and SIVmac251 each exhibit modest within-isolate genetic heterogeneity, with 1.8% and 2.6% maximum diversity for SIVsmE660 and SIVmac251, respectively. The genetic distance between the SIVsmE660 and SIVmac251 lineages in is substantially greater, 14.6% in nucleotide sequence and a 13.5% difference in amino acid sequence, based on uncorrected mean character differences. This interlineage diversity has made these virus strains attractive candidates for heterologous Halofuginone challenge studies of candidate HIV vaccines. Uncloned challenge stocks of SIVsmE660 and SIVmac251 have been used to test various vaccine.