SIVcpz from a naturally infected Cameroonian chimpanzee: Biological and genetic comparison with HIV‐1 N

179

135

Simian immunodeficiency viruses (SIVs) are primate lentiviruses that infect no fewer than 36 different nonhuman primate species in sub-Saharan Africa (4,9,62). Two of these viruses, SIVcpz from chimpanzees (Pan troglodytes) and SIVsmm from sooty mangabeys (Cercocebus atys), have crossed species barriers on multiple occasions and have generated human immunodeficiency virus (HIV) types 1 and 2 (20,24,25,94). AIDS, one of the most devastating infectious diseases to have emerged in recent history, is thus the result of cross-species infections of humans by lentiviruses of primate origin (33).Identification of the primate source that spawned the HIV-1 pandemic is of scientific and public health importance. To this end, it is now well established that the immediate precursor of HIV-1 is a lentivirus that infects chimpanzees of the subspecies Pan troglodytes troglodytes in west central Africa (17,24). What is also known but perhaps less widely appreciated is that SIVcpz strains have been transmitted to humans on at least three independent occasions and that the current HIV-1 group M pandemic, which has afflicted more than 60 million people and caused more than 20 million deaths, resulted from just one of these transmission events in the first half of the twentieth century (42,77,97). The reasons for HIV-1's sudden emergence, the adaptive changes that followed, and the mechanisms underlying its unique pathogenicity in humans have not yet been determined.Primates naturally infected with SIV, including SIVcpz-infected chimpanzees, appear not to develop immunodeficiency or AIDS (31,40,49,60,70,79). In contrast, HIV infection of humans is nearly always characterized by progressive loss of CD4 ϩ T lymphocytes, chronic immune activation, and gradual destruction of an array of immune functions (82). The basis for this difference in pathogenicity is not understood, but deciphering which viral and/or host factors are responsible for the nonpathogenic course of natural SIV infections could well prove useful in developing more-effective treatment or prevention strategies for HIV/AIDS.Chimpanzees and humans share more than 98% sequence identity across their genomes (91). This degree of relatedness provides a unique opportunity to search for key differences in virus-host interactions responsible for differences in viral pathogenicity, an approach that could prove complementary to current studies that focus primarily on human disease susceptibility (55). In this review, we summarize recent progress in four key scientific areas related to AIDS pathogenesis: (i) the origin of HIV-1; (ii) the origin of SIVcpz; (iii) natural SIVcpz reservoirs; and (iv) the natural history of SIVcpz infection. Scientific and public health implications of these data as they relate to human infections by the corresponding virus, HIV-1, will also be discussed.

Section: The Origin Of Hiv-1mentioning

confidence: 99%

Section: The Origin Of Hiv-1mentioning

confidence: 99%

Simian Immunodeficiency Virus Infection of Chimpanzees

Sharp

Shaw

Hahn³

2005

179

135

“…In order to determine whether this deletion in exon III is present or not in other African nonhuman primates, we examined genomic DNA of 13 animals from five distinct species: patas monkey (Erythrocebus patas), l'Hoest monkey (Cercopithecus lhoesti), white-collared mangabey (Cercocebus torquatus lunulatus), gray-cheeked mangabey (Cercocebus albigena), and chimpanzee (Pan troglodytes troglodytes) (33). The latter corresponds to a naturally SIVcpz-infected chimpanzee (Cam5) (34). We observed again a smaller amplicon, indicating the same deletion in all of the animals studied (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Patas monkeys (Erythrocebus patas) were held in captivity at the Pasteur Institute in Bangui. L'Hoest's monkeys (Cercopithecus lhoesti lhoesti), white-collared mangabeys (Cercocebus torquatus lunulatus), gray-cheeked mangabeys (Cercocebus albigena), and a naturally SIVcpz-infected chimpanzee (Pan troglodytes, Cam5) were housed in European and Cameroonian zoos (33,34). Rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) macaques were housed at the primate center of CEA, Fontenay aux Roses, France.…”

Section: Methodsmentioning

confidence: 99%

DC-SIGN from African Green Monkeys Is Expressed in Lymph Nodes and Mediates Infection intransof Simian Immunodeficiency Virus SIVagm

Ploquin¹,

Diop

Sol‐Foulon³

et al. 2004

African green monkeys (AGMs) infected by simian immunodeficiency virus (SIV) SIVagm are resistant to AIDS. SIVagm-infected AGMs exhibit levels of viremia similar to those described during pathogenic human immunodeficiency virus type 1 (HIV-1) and SIVmac infections in humans and macaques, respectively, but contain lower viral loads in their lymph nodes. We addressed the potential role of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN; CD209) in viral dissemination. In previous studies, it has been shown that human DC-SIGN and macaque DC-SIGN allow transmission of HIV and SIVmac to T cells. Here, we looked at the ability of DC-SIGN derived from AGM lymph nodes to interact with SIVagm. We show that DC-SIGN-expressing cells are present mainly in the medulla and often within the cortex and/or paracortex of AGM lymph nodes. We describe the isolation and characterization of at least three isoforms of dc-sign mRNA in lymph nodes of AGMs. The predicted amino acid sequence from the predominant mRNA isoform, DC-SIGNagm1, is 92 and 99% identical to the corresponding human and rhesus macaque DC-SIGN amino acid sequences, respectively. DC-SIGNagm1 is characterized by the lack of the fourth motif in the repeat domain. This deletion was also detected in the dc-sign gene derived from thirteen animals belonging to five other African monkey species and from four macaques (Macaca fascicularis and M. mulatta). Despite three-to seven-amino-acid modifications compared to DC-SIGNmac, DC-SIGNagm1 allows transmission of SIVagm to T cells. Furthermore, AGM monocyte-derived dendritic cells (MDDC) expressed at least 100,000 DC-SIGN molecules and were able to transmit SIVagm to T cells. At a low multiplicity of infection (10 ؊5 50% tissue culture infective doses/cell), viral transmission by AGM MDDC was mainly DC-SIGN dependent. The present study reveals that DC-SIGN from a natural host species of SIV has the ability to act as an efficient attachment and transmission factor for SIVagm and suggests the absence of a direct link between this ability and viral load levels in lymph nodes.

“…The HIV-1 N YBF30 and YBF116 (3,74) nef alleles were also amplified from PBMC. The SIVcpz US (20) (14) and Cam5 (14,48) with human PBMC. The remaining SIVcpz nef alleles were amplified from plasma RNA derived from Noah (ch-No) and an uncultured PBMC sample derived from Niko (ch-Ni), respectively.…”

Section: Methodsmentioning

confidence: 99%

Nef Proteins from Simian Immunodeficiency Virus-Infected Chimpanzees Interact with p21-Activated Kinase 2 and Modulate Cell Surface Expression of Various Human Receptors

Kirchhoff¹,

Schindler²,

Bailer³

et al. 2004

The accessory Nef protein allows human immunodeficiency virus type 1 (HIV-1) to persist at high levels and to cause AIDS in infected humans. The function of HIV-1 group M subtype B nef alleles has been extensively studied, and a variety of in vitro activities believed to be important for viral pathogenesis have been established. However, the function of nef alleles derived from naturally simian immunodeficiency virus (SIV)-infected chimpanzees, the original host of HIV-1, or from the HIV-1 N and O groups resulting from independent zoonotic transmissions remains to be investigated. In the present study we demonstrate that SIVcpz and HIV-1 group N or O nef alleles down-modulate CD4, CD28, and class I or II MHC molecules and up-regulate surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II. Furthermore, the ability of Nef to interact with the p21-activated kinase 2 was generally conserved. The functional activity of HIV-1 group N and O nef genes did not differ significantly from group M nef alleles. However, SIVcpz nef genes as a group showed a 1.8-and 2.0-fold-higher activity in modulating CD28 (P ‫؍‬ 0.0002) and Ii (P ‫؍‬ 0.016) surface expression, respectively, but were 1.7-fold less active in down-regulating MHC class II molecules (P ‫؍‬ 0.006) compared to HIV-1 M nef genes. Our finding that primary SIVcpz nef alleles derived from naturally infected chimpanzees modulate the surface expression of various human cellular receptors involved in T-cell activation and antigen presentation suggests that functional nef genes helped the chimpanzee virus to persist efficiently in infected humans immediately after zoonotic transmission.