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SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys.

Humbert M, Rasmussen RA, Song R, Ong H, Sharma P, Chenine AL, Kramer VG, Siddappa NB, Xu W, Else JG, Novembre FJ, Strobert E, O'Neil SP, Ruprecht RM - Retrovirology (2008)

Bottom Line: We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype.Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123-270 weeks post-exposure.Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. michael_humbert@dfci.harvard.edu

ABSTRACT

Background: Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates. SHIV challenges allow assessment of anti-HIV-1 envelope responses in primates. As such, SHIVs should mimic natural HIV-1 infection in humans and, to address the pandemic, encode HIV-1 Env components representing major viral subtypes worldwide.

Results: We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype. The parental infectious proviral clone, SHIV-1157i, was rapidly passaged through five rhesus monkeys. After AIDS developed in the first animal at week 123 post-inoculation, infected blood was infused into a sixth monkey. Virus reisolated at this late stage was still exclusively R5 tropic and mucosally transmissible. Here we describe the long-term follow-up of this initial cohort of six monkeys. Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123-270 weeks post-exposure. Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis.

Conclusion: These data document the disease progression induced by the first mucosally transmissible, pathogenic R5 non-clade B SHIV and suggest that SHIV-1157i-derived viruses, including the late-stage, highly replication-competent SHIV-1157ipd3N4 previously described (Song et al., 2006), display biological characteristics that mirror those of HIV-1 clade C and support their expanded use for AIDS vaccine studies in nonhuman primates.

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Serial passage of SHIV-1157i in rhesus monkeys for viral adaptation. The first animal was inoculated i.v. with cell-free supernatant from 293T cells transfected with the infectious molecular clone SHIV-1157i; subsequent animals were inoculated i.v. through serial blood transfer. The neonatal period comprises birth to one month; infancy the period up to one year, and juvenile monkeys are aged between one and five years.
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Figure 1: Serial passage of SHIV-1157i in rhesus monkeys for viral adaptation. The first animal was inoculated i.v. with cell-free supernatant from 293T cells transfected with the infectious molecular clone SHIV-1157i; subsequent animals were inoculated i.v. through serial blood transfer. The neonatal period comprises birth to one month; infancy the period up to one year, and juvenile monkeys are aged between one and five years.

Mentions: The details of the molecular cloning and biological characterization of SHIV-1157i have been previously published [8]. For the rapid animal-to-animal passage of SHIV-1157i, we used five rhesus monkeys (RM); the first animal was inoculated with 6 ml of cell-free virus obtained from 293T cells transfected with the infectious molecular clone, SHIV-1157i (Figure 1). At week 1 post-inoculation (p.i.), plasma viral RNA (vRNA) loads were measured and if found to be ≥ 104 copies/ml, 1 ml whole blood was transfused to the next animal a week later, the time point of the expected peak viremia (Figure 1). Plasma vRNA loads, absolute numbers of CD4+ T cells, percentage CD4+CD29+ memory T cells, and CD4:CD8 T-cell ratios were monitored longitudinally in peripheral blood in all RM. The five RM from the initial virus passage were divided into two groups: progressors (RPn-8, RTs-7, RKl-8) and non-progressors (RAo-8, RIl-8) (Figure 2). Both groups showed an initial peak of viremia within the first 2 weeks p.i. and seroconverted within 6 weeks. Compared to the first virus recipient, RPn-8, the four subsequent RM had peak vRNA loads that were 1–2 logs higher. After seroconversion, the progressors remained viremic with plasma vRNA levels ranging from 103 to 5 × 106 copies/ml, although plasma vRNA levels were occasionally undetectable in RTs-7 (Figure 2A). In contrast, the non-progressors controlled viremia after the initial high peak vRNA levels, and remained aviremic except for occasional blips that did not exceed 103 copies/ml (Figure 2B). Overall, the viral set points of the progressors were 1–4 logs higher compared to non-progressors; among progressors, only RTs-7 showed a relatively low vRNA level, with a setpoint of 104 copies or less/ml plasma throughout the latter portion of the observation period (Fig 2A).


SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys.

Humbert M, Rasmussen RA, Song R, Ong H, Sharma P, Chenine AL, Kramer VG, Siddappa NB, Xu W, Else JG, Novembre FJ, Strobert E, O'Neil SP, Ruprecht RM - Retrovirology (2008)

Serial passage of SHIV-1157i in rhesus monkeys for viral adaptation. The first animal was inoculated i.v. with cell-free supernatant from 293T cells transfected with the infectious molecular clone SHIV-1157i; subsequent animals were inoculated i.v. through serial blood transfer. The neonatal period comprises birth to one month; infancy the period up to one year, and juvenile monkeys are aged between one and five years.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2576354&req=5

Figure 1: Serial passage of SHIV-1157i in rhesus monkeys for viral adaptation. The first animal was inoculated i.v. with cell-free supernatant from 293T cells transfected with the infectious molecular clone SHIV-1157i; subsequent animals were inoculated i.v. through serial blood transfer. The neonatal period comprises birth to one month; infancy the period up to one year, and juvenile monkeys are aged between one and five years.
Mentions: The details of the molecular cloning and biological characterization of SHIV-1157i have been previously published [8]. For the rapid animal-to-animal passage of SHIV-1157i, we used five rhesus monkeys (RM); the first animal was inoculated with 6 ml of cell-free virus obtained from 293T cells transfected with the infectious molecular clone, SHIV-1157i (Figure 1). At week 1 post-inoculation (p.i.), plasma viral RNA (vRNA) loads were measured and if found to be ≥ 104 copies/ml, 1 ml whole blood was transfused to the next animal a week later, the time point of the expected peak viremia (Figure 1). Plasma vRNA loads, absolute numbers of CD4+ T cells, percentage CD4+CD29+ memory T cells, and CD4:CD8 T-cell ratios were monitored longitudinally in peripheral blood in all RM. The five RM from the initial virus passage were divided into two groups: progressors (RPn-8, RTs-7, RKl-8) and non-progressors (RAo-8, RIl-8) (Figure 2). Both groups showed an initial peak of viremia within the first 2 weeks p.i. and seroconverted within 6 weeks. Compared to the first virus recipient, RPn-8, the four subsequent RM had peak vRNA loads that were 1–2 logs higher. After seroconversion, the progressors remained viremic with plasma vRNA levels ranging from 103 to 5 × 106 copies/ml, although plasma vRNA levels were occasionally undetectable in RTs-7 (Figure 2A). In contrast, the non-progressors controlled viremia after the initial high peak vRNA levels, and remained aviremic except for occasional blips that did not exceed 103 copies/ml (Figure 2B). Overall, the viral set points of the progressors were 1–4 logs higher compared to non-progressors; among progressors, only RTs-7 showed a relatively low vRNA level, with a setpoint of 104 copies or less/ml plasma throughout the latter portion of the observation period (Fig 2A).

Bottom Line: We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype.Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123-270 weeks post-exposure.Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. michael_humbert@dfci.harvard.edu

ABSTRACT

Background: Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates. SHIV challenges allow assessment of anti-HIV-1 envelope responses in primates. As such, SHIVs should mimic natural HIV-1 infection in humans and, to address the pandemic, encode HIV-1 Env components representing major viral subtypes worldwide.

Results: We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype. The parental infectious proviral clone, SHIV-1157i, was rapidly passaged through five rhesus monkeys. After AIDS developed in the first animal at week 123 post-inoculation, infected blood was infused into a sixth monkey. Virus reisolated at this late stage was still exclusively R5 tropic and mucosally transmissible. Here we describe the long-term follow-up of this initial cohort of six monkeys. Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123-270 weeks post-exposure. Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis.

Conclusion: These data document the disease progression induced by the first mucosally transmissible, pathogenic R5 non-clade B SHIV and suggest that SHIV-1157i-derived viruses, including the late-stage, highly replication-competent SHIV-1157ipd3N4 previously described (Song et al., 2006), display biological characteristics that mirror those of HIV-1 clade C and support their expanded use for AIDS vaccine studies in nonhuman primates.

Show MeSH
Related in: MedlinePlus