Derivation and characterization of a highly pathogenic isolate of human immunodeficiency virus type 2 that causes rapid CD4<sup>+</sup> cell depletion in <i>Macaca nemestrina</i>

Similar to human immunodeficiency virus type 1 (HIV-1) infection of humans, the natural history of HIV-2 infection in baboons (Papio cynocephalus) is a slow and chronic disease that generally takes several years before an AIDS-like condition develops. To shorten the amount of time to the development of disease, we performed five serial passages of HIV-2 UC2 in baboons by using blood and bone marrow samples during the acute phase of infection when viral loads were at high levels. After these serial passages, virus levels in plasma, peripheral blood mononuclear cells (PBMC) and lymphatic tissues in the acutely infected baboons were increased. Within 1 year of the HIV-2 infection, all of the inoculated baboons showed specific signs of AIDS-related disease progression within the lymphatic tissues, such as vascular proliferation and lymphoid depletion. The HIV-2 UC2 recovered after four serial passages showed increased kinetics of viral replication in baboon PBMC and cytopathicity. This study suggests that the HIV-2 isolate recovered after several serial passages in baboons will be useful in future studies of AIDS pathogenesis and vaccine development by using this animal model.

Section: Discussionmentioning

confidence: 61%

“…HIV-1 and HIV-2 isolates have been inoculated into several nonhuman primates (1,11,18,33,40), but with HIV-2, only baboons (Papio cynocephalus) and pig-tailed macaques develop an AIDS-like disease (3,28,31,32). The infection course in baboons resembles the slow, lentiviral disease progression that is observed in chronic HIV-1 infection in humans.…”

mentioning

confidence: 99%

Increased Virus Replication and Virulence after Serial Passage of Human Immunodeficiency Virus Type 2 in Baboons

Locher

Witt

Herndier

et al. 2003

“…Our laboratory has shown that Macaca nemestrina animals are susceptible to infection with a primary HIV-2 isolate, HIV-2/EHO (14,25). M. nemestrina macaques have also been reported to be susceptible to some HIV-1 isolates (1,(4)(5)(6)(7)19) although this idea remains controversial.…”

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confidence: 90%

Novel TRIM5 Isoforms Expressed byMacaca nemestrina

Brennan

Kozyrev

Kodama

et al. 2007

Self Cite

The TRIM5 family of proteins contains a RING domain, one or two B boxes, and a coiled-coil domain. The TRIM5␣ isoform also encodes a C-terminal B30.2(SPRY) domain, differences within which define the breadth and potency of TRIM5␣-mediated retroviral restriction. Because Macaca nemestrina animals are susceptible to some human immunodeficiency virus (HIV) isolates, we sought to determine if differences exist in the TRIM5 gene and transcripts of these animals. We identified a two-nucleotide deletion (⌬2) in the transcript at the 5 terminus of exon 7 in all M. nemestrina TRIM5 cDNA clones examined. This frameshift results in a truncated protein of 300 amino acids lacking the B30.2(SPRY) domain, which we have named TRIM5. This deletion is likely due to a single nucleotide polymorphism that alters the 3 splice site between intron 6 and exon 7. In some clones, a deletion of the entire 27-nucleotide exon 7 (⌬exon7) resulted in the restoration of the TRIM5 open reading frame and the generation of another novel isoform, TRIM5. There are 18 amino acid differences between M. nemestrina TRIM5 and Macaca mulatta TRIM5␣, some of which are at or near locations previously shown to affect the breadth and potency of TRIM5␣-mediated restriction. Infectivity assays performed on permissive CrFK cells stably transduced with TRIM5 or TRIM5 show that these isoforms are incapable of restricting either HIV type 1 (HIV-1) or simian immunodeficiency virus infection. The expression of TRIM5 alleles incapable of restricting HIV-1 infection may contribute to the previously reported increased susceptibility of M. nemestrina to HIV-1 infection in vivo. The human immunodeficiency virus (HIV) pandemic is the result of cross-species transmissions of simian immunodeficiency virus (SIV) from non-human primates to humans (28).The recent discovery of human T-cell leukemia virus types 3 and 4 suggests that cross-species transmission of retroviruses is not an infrequent occurrence (33). However, to establish a productive infection in a new species, it is necessary for retroviruses to evade host-specific restriction factors. A broad range of antiretroviral host restriction factors has been identified in mammalian species. The best-described primate host restriction factors are APOBEC3F/G and TRIM5␣. APOBEC3F/G are cytidine deaminases which exert a late block to retroviral replication, inhibiting the virus in target cells rather than producer cells (29), whereas TRIM5␣ exerts a dominant block to infection immediately after viral entry into the cell through the inhibition of reverse transcription (30).TRIM5␣ is a member of the tripartite motif family of proteins, also called RBCC proteins, because of the presence of a RING domain (C3HC4 type), one or two B boxes, and a coiled-coil region in an ordered arrangement from N terminus to C terminus (23). Six isoforms of TRIM5 have been identified in mammals (26). These proteins have been shown to form homo-and heteromultimers, although only homomultimers of TRIM5␣ have been shown to restrict lentiviruses (3,8,15,...

“…Importantly, in contrast to other nonhuman primate models, PTM are susceptible to many lentiviral infections other than SIV and SHIV, including infection with HIV-1, HIV-2, and simian tropic (stHIV-1) (1,3,6,24,29,42,49,55,60), which makes this model invaluable for vaccination and pathogenesis studies. Furthermore, recent characterization of APOBEC and TRIM5␣ genes in PTM has allowed for the development of minimally chimeric stHIV-1 strains, differing from HIV-1 only in vif genes, that persistently infect PTM due to the TRIMCyp fusion protein which PTM harbor rather than TRIM5 (11,21,60).…”

mentioning

confidence: 99%

Dynamics of Simian Immunodeficiency Virus SIVmac239 Infection in Pigtail Macaques

Klatt

Canary

Vanderford

et al. 2012

Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P ‫؍‬ 0.0018). However, increased SIV progression was not associated with increased viremia, as both peak and set-point plasma viremias were similar between PTM and RM (P ‫؍‬ 0.7953 and P ‫؍‬ 0.1006, respectively). Moreover, this increased disease progression was not associated with rapid CD4 ؉ T cell depletion, as CD4 ؉ T cell decline resembled other SIV/human immunodeficiency virus (HIV) models. Since immune activation is the best predictor of disease progression during HIV infection, we analyzed immune activation by turnover of T cells by BrdU decay and Ki67 expression. We found increased levels of turnover prior to SIV infection of PTM compared to that observed with RM, which may contribute to their increased disease progression rate. These data evaluate the kinetics of SIVmac239-induced disease progression and highlight PTM as a model for HIV infection and the importance of immune activation in SIV disease progression.