Elucidation of the phylogenetic origins of simian and human immunodeficiency viruses (SIV and HIV) is fundamental to the understanding of HIV pathogenesis and the spread of AIDS worldwide. In this study, we molecularly characterized multiple SIVAGM isolates from four different African green monkey species (vervet, grivet, sabaeus and tantalus monkeys). Phylogenetic analysis of partial (1 kb) env sequences indicated that all SIVAGM strains cluster together, and that they fall into four distinct sequence sub‐groups according to their species of origin. However, alignment of long terminal repeat sequences revealed that SIVs from West African sabaeus monkeys contain a structural feature (a duplication of the transactivation response element) thus far only found in otherwise highly divergent lentiviruses infecting sooty mangabeys (SIVSM) and humans (HIV‐2). To determine whether there were additional similarities with the SIVSM/HIV‐2 group, a full‐length replication competent sabaeus provirus was cloned and sequenced. In phylogenetic trees derived from the central and 3′ coding regions, the sabaeus virus clustered with SIVAGM isolates from other African green monkey species. However, in trees derived from the 3′ half of gag and the adjacent 5′ region of pol, the sabaeus virus grouped with the SIVSM/HIV‐2 lineage. These results indicated that the sabaeus virus comprised a mosaic genome which must have resulted from recombination of divergent lentiviruses in the distant past. A second, independent sabaeus isolate exhibited similar phylogenetic relationships, suggesting that all West African green monkey viruses share this complex evolutionary history. Taken together, these results indicate that African green monkeys have been infected with SIVAGM for very long periods of time, and that recombination and cross‐species transmission in the wild have contributed to the genetic complexity of primate lentiviruses.

The design of an effective AIDS vaccine has eluded the efforts of the scientific community to the point that alternative approaches to classic vaccine formulations have to be considered. We propose here that HIV vaccine research could greatly benefit from the study of natural simian immunodeficiency virus (SIV) infections of African nonhuman primates. Natural SIV hosts (for example, sooty mangabeys, African green monkeys and mandrills) share many features of HIV infection of humans; however, they usually do not develop immunodeficiency. These natural, nonprogressive SIV infections represent an evolutionary adaptation that allows a peaceful coexistence of primate lentiviruses and the host immune system. This adaptation does not result in reduced viral replication but, rather, involves phenotypic changes to CD4+ T cell subsets, limited immune activation and preserved mucosal immunity, all of which contribute to the avoidance of disease progression and, possibly, to the reduction of vertical SIV transmission. Here we summarize the current understanding of SIV infection of African nonhuman primates and discuss how unraveling these evolutionary adaptations may provide clues for new vaccine designs that might induce effective immune responses without the harmful consequences of excessive immune activation.

African green monkeys can maintain long-term persistent infection with simian immunodeficiency viruses (SIVagm) without developing AIDS and thus provide an important model for understanding mechanisms of natural host resistance to disease. This study assessed the levels and anatomic distribution of SIVagm in healthy, naturally infected monkeys. Quantitative competitive reverse transcriptase PCR assays developed to measure SIVagm from two African green monkey subspecies demonstrated high levels of SIV RNA in plasma (>6 ؋ 10 6 RNA copies/ml) in sabaeus and vervet monkeys. Infectious virus was readily recovered from plasma and peripheral blood mononuclear cells and shown to be highly cytopathic in human cell lines and macrophages. SIVagm DNA levels were highest in the gastrointestinal tract, suggesting that the gut is a major site for SIVagm replication in vivo. Appreciable levels of virus were also found within the brain parenchyma and the cerebrospinal fluid (CSF), with lower levels detected in peripheral blood cells and lymph nodes. Virus isolates from the CSF and brain parenchyma readily infected macrophages in culture, whereas lymph node isolates were more restricted to growth in human T-cell lines. Comparison of env V2-C4 sequences showed extensive amino acid diversity between SIVagm recovered from the central nervous system and that recovered from lymphoid tissues. Homology between brain and CSF viruses, macrophage tropism, and active replication suggest compartmentalization in the central nervous system without associated neuropathology in naturally infected monkeys. These studies provide evidence that the nonpathogenic nature of SIVagm in the natural host can be attributed neither to more effective host control over viral replication nor to differences in the tissue and cell tropism from those for human immunodeficiency virus type 1-infected humans or SIV-infected macaques.

We describe the first reported transmission to a human of simian foamy virus (SFV) from a free-ranging population of nonhuman primates in Asia. The transmission of an exogenous retrovirus, SFV, from macaques ( Macaca fascicularis ) to a human at a monkey temple in Bali, Indonesia, was investigated with molecular and serologic techniques. Antibodies to SFV were detected by Western blotting of serum from 1 of 82 humans tested. SFV DNA was detected by nested polymerase chain reaction (PCR) from the blood of the same person. Cloning and sequencing of PCR products confirmed the virus's close phylogenetic relationship to SFV isolated from macaques at the same temple. This study raises concerns that persons who work at or live around monkey temples are at risk for infection with SFV.

Polymorphisms in CC chemokine receptor 5 (CCR5), the major coreceptor of human immunodeficiency virus 1 (HIV-1) and simian immunodeficiency virus (SIV), have a major influence on HIV-1 transmission and disease progression. The effects of these polymorphisms may, in part, account for the differential pathogenesis of HIV-1 (immunosuppression) and SIV (natural resistance) in humans and non-human primates, respectively. Thus, understanding the genetic basis underlying species-specific responses to HIV-1 and SIV could reveal new anti-HIV-1 therapeutic strategies for humans. To this end, we compared CCR5 structure/evolution and regulation among humans, apes, Old World Monkeys, and New World Monkeys. The evolution of the CCR5 cis-regulatory region versus the open reading frame as well as among different domains of the open reading frame differed from one another. CCR5 cis-regulatory region sequence variation in humans was substantially higher than anticipated. Based on this variation, CCR5 haplotypes could be organized into seven evolutionarily distinct human haplogroups (HH) that we designated HHA, -B, -C, -D, -E, -F, and -G. HHA haplotypes were defined as ancestral to all other haplotypes by comparison to the CCR5 haplotypes of non-human primates. Different human and non-human primate CCR5 haplotypes were associated with differential transcriptional regulation, and various polymorphisms resulted in modified DNA-nuclear protein interactions, including altered binding of members of the NF-B family of transcription factors. We identified novel CCR5 untranslated mRNA sequences that were conserved in human and non-human primates. In some primates, mutations at exon-intron boundaries caused loss of expression of selected CCR5 mRNA isoforms or production of novel mRNA isoforms. Collectively, these findings suggest that the response to HIV-1 and SIV infection in primates may have been driven, in part, by evolution of the elements controlling CCR5 transcription and translation.