SOME HIV 1 VPU PROTEINS ARE ABLE TO ANTAGONIZE MACAQUE BST-2 IN VITRO AND IN VIVO. The HIV-1 Vpu protein enhances the release of viral particles from infected cells by targeting BST-2/Tetherin, a cellular protein inhibiting virus release. The widely used HIV-1NL4-3 Vpu functionally inactivates human BST-2 but not rhesus monkey BST-2, leading to the notion that Vpu antagonism is species-specific. Our study was motivated by the observation that during the serial passaging of the CXCR4 (X4) tropic SHIVDH12, the pathogenic virus, which emerged (SHIVDH12R) and its molecularly cloned derivative SHIVDH12-CL7, carried a vpu gene that differed genetically from the homologue present in HIV 1NL4-3. This led us to investigate whether the Vpu encoded by SHIVDH12-CL7, despite its presumed inability to target macaque BST-2 might contribute to the augmented pathogenic potential observed in inoculated rhesus macaques. Surprisingly, we found that the SHIVDH12-CL7 Vpu protein was able to functionally inactivate rhesus BST-2 in ex vivo assays while retaining its activity against human BST-2. We also observed that the expanded host range of SHIVDH12-CL7 Vpu was not the result of serial passaging in monkeys but was an intrinsic property of the Vpu protein encoded by the parental HIVDH12 isolate. At the organismal level, a majority of monkeys inoculated with Vpu defective X4 or R5 tropic SHIVs generated lower set point viremia, exhibited better maintenance of CD4+ T lymphocyte levels, and experienced delayed disease onset compared to SHIVs carrying wild-type vpu genes. Taken together, these results suggest that HIV-1 Vpu proteins are functionally different and that the inability of the prototypic HIV 1NL4-3 Vpu to inhibit macaque BST-2 may not be a typical property of Vpu proteins encoded by primary HIV-1 isolates. RECOMBINATION MEDIATED CHANGES IN CORECEPTOR USAGE CONFERS AN AUGMENTED PATHOGENIC PHENOTYPE IN A NON-HUMAN PRIMATE MODEL OF HIV 1 INDUCED AIDS. Evolution of the env gene in transmitted R5-tropic HIV 1 strains is the most widely accepted mechanism driving coreceptor switching. In some infected individuals, however, a shift in coreceptor utilization can occur as a result of the re-emergence of a co-transmitted, but rapidly controlled, X4 virus. The latter possibility was studied by dually infecting rhesus macaques with X4 and R5 SHIVs and monitoring the replication status of each virus using specific primer pairs. In one of the infected monkeys, both SHIVs were potently suppressed by week 12 post inoculation but a burst of viremia at week 51 was accompanied by an unrelenting loss of total CD4+ T cells and the development of clinical disease. PCR analyses of plasma viral RNA indicated an env gene segment, containing the V3 region from the inoculated X4 SHIV, had been transferred into the genetic background of the input R5 SHIV by intergenomic recombination, creating an X4 virus with novel replicative, serological, and pathogenic properties. These results indicate that the effects of retrovirus recombination in vivo can be functionally profound and may even occur when one of the recombination participants is undetectable in the circulation as cell free virus.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$1,380,625
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Shingai, Masashi; Welbourn, Sarah; Brenchley, Jason M et al. (2015) The Expression of Functional Vpx during Pathogenic SIVmac Infections of Rhesus Macaques Suppresses SAMHD1 in CD4+ Memory T Cells. PLoS Pathog 11:e1004928
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Shingai, Masashi; Yoshida, Takeshi; Martin, Malcolm A et al. (2011) Some human immunodeficiency virus type 1 Vpu proteins are able to antagonize macaque BST-2 in vitro and in vivo: Vpu-negative simian-human immunodeficiency viruses are attenuated in vivo. J Virol 85:9708-15
Nishimura, Yoshiaki; Shingai, Masashi; Willey, Ronald et al. (2010) Generation of the pathogenic R5-tropic simian/human immunodeficiency virus SHIVAD8 by serial passaging in rhesus macaques. J Virol 84:4769-81
Klatt, N R; Harris, L D; Vinton, C L et al. (2010) Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection. Mucosal Immunol 3:387-98

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