Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity—yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research. Am. J. Primatol. 76:801–827, 2014. © 2014 Wiley Periodicals, Inc.

Primates have evolved a variety of restriction factors that prevent retroviral replication. One such factor, TRIM5␣, mediates a postentry restriction in many Old World primates. Among New World primates, Aotus trivirgatus exerts a similar early restriction mediated by TRIMCyp, a TRIM5-cyclophilin A (CypA) chimera resulting from a CypA retrotransposition between exons 7 and 8 of the TRIM5 gene. convergent evolution ͉ cyclophilin A ͉ HIV ͉ retroviruses ͉ TRIM5␣ T he current HIV pandemic resulting from cross-species transmissions of simian immunodeficiency viruses SIVcpz or SIVsmm to humans has been well documented (1). However, the mechanisms enabling such transmissions are not yet fully understood. Mammals have evolved several restriction factors capable of inhibiting the replication of certain retroviruses in a species-specific manner. One of the best described primate host-restriction factors is TRIM5␣, which is expressed in most Old World primates.Macaca mulatta TRIM5␣ exerts an early, postentry block to HIV-1 replication (2). TRIM5␣ is a member of the tripartite motif family of proteins, characterized by the ordered Nterminal to C-terminal expression of a RING domain, B-Box, and coiled coil, also known as an RBCC domain (3). The TRIM5␣ isoform also expresses a B30.2 domain at the C terminus, which is required for recognition of the incoming retroviral capsid (4-7). Changes to the B30.2 domain have been shown to dramatically affect the breadth and potency of TRIM5␣-mediated anti-retroviral activity. For instance, the ability to restrict HIV-1 replication may be conferred to Homo sapiens TRIM5␣ by changing a single residue to the amino acid found in M. mulatta TRIM5␣, R332P (8). Similarly, site-directed mutagenesis studies have demonstrated that mutations around the cyclophilin A (CypA) binding loop of HIV-1 capsid effect the potency of TRIM5␣-mediated restriction, suggesting that the B30.2 domain interacts with or near the CypA binding loop (5, 9, 10).New World primates Aotus trivirgatus exert a postentry restriction to HIV-1 mediated by a TRIM5-CypA chimera. Sequencing the A. trivirgatus TRIM5 gene identified a LINE-1-mediated retrotransposition of CypA into intron 7, resulting in the expression of a fusion protein called TRIMCyp, which is unique to the Aotus genus (11-13). TRIMCyp retains the N-terminal tripartite motif of all TRIM family members, but the B30.2 domain of TRIM5␣ is replaced by the CypA domain. Functionally, TRIM5␣ and TRIMCyp are similar, preventing reverse transcription of incoming viruses at an early postentry stage. However, TRIMCyp exerts a more potent restriction to incoming retroviruses than TRIM5␣, and unlike TRIM5␣, TRIMCyp-mediated restriction is sensitive to cyclosporin A. A. trivirgatus has been shown to express only TRIMCyp,.We recently demonstrated that the Old World primates Macaca nemestrina do not express TRIM5␣. Instead, they transcribe novel isoforms TRIM5 and TRIM5 (14). These isoforms likely arise because of a single-nucleotide polymorphism (SNP) at the intron 6 splice acc...

The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian–human immunodeficiency virus (SHIV) challenge. Systems serology of the antibody responses identifies plasma antibody binding to HIV-infected cells, peak ADCC antibody titres, NK cell-mediated ADCC and antibody-mediated activation of MIP-1β in NK cells as the four immunological parameters that best predict decreased infection risk that are improved by the pentavalent vaccine. Thus inclusion of additional gp120 immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques.