Construction and characterisation of infectious recombinant HIV-1 clones containing CTL epitopes from structural proteins in Nef

Guillon, Christophe; Baalen, Carel A. van; Boers, Patrick H. M.; Verschuren, Esther J.; Gruters, Rob A.; Osterhaus, Albert D. M. E.

doi:10.1016/s0166-0934(01)00389-5

Cited by 5 publications

(6 citation statements)

References 30 publications

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“…HIV‐1 2.1RN contains the RT‐epitope recognized by the RT‐CTL used in this study, and HIV 1 2.1EN contains a previously described Env‐epitope 25. Insertion of the epitopes did not perturb production of full‐length Nef 21 or Nef‐mediated down‐modulation of HLA class I expression on the cell surface (data not shown). Cells expressing the recombinant Nef proteins were recognized by their cognate CTL 21, indicating that the epitopes were correctly processed and presented.…”

Section: Resultsmentioning

confidence: 79%

“…Insertion of the epitopes did not perturb production of full‐length Nef 21 or Nef‐mediated down‐modulation of HLA class I expression on the cell surface (data not shown). Cells expressing the recombinant Nef proteins were recognized by their cognate CTL 21, indicating that the epitopes were correctly processed and presented. Both HIV‐1 2.1RN and HIV‐1 2.1EN replicated with similar kinetics as HIV‐1 2.1WT (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…The virus used, HIV-1 ACH320.2A.2.1 (HIV-1 2.1WT ) was detectable from day 4 onwards and increased exponentially over a 3 log 10 range, until a plateau was reached by day 9 (Fig. 1a) [21] cf. [22].…”

Section: Inhibition Of Hiv Reproduction By Ctlmentioning

confidence: 99%

“…To test this in vitro, we constructed recombinant viruses containing sequences encoding epitopes derived from late proteins inserted into the early expressed nef gene [21]. HIV-1 2.1RN contains the RT-epitope recognized by the RT-CTL used in this study, and HIV 1 2.1EN contains a previously described Env-epitope [25].…”

Section: Impact Of Epitope Expression Kinetics On Ctl Effectiveness In Vitromentioning

confidence: 99%

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Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes

et al. 2002

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Recent studies indicate that the time required for virus‐infected cells to become vulnerable for the activity of CTL is of significance for the capacity of CTL to control ongoing viral reproduction. To investigate whether this applies to the effectiveness of HIV‐1‐specific CTL, we measured virus production in cultures containing CD4+ T cells inoculated with HIV at low multiplicity of infection, and CTL directed against an early protein, Rev, or a late protein, RT. The Rev‐specific CTL prevented at least 2 log10 more HIV‐1 production, in 10 days, than similar numbers of RT‐specific CTL. To study how CTL effectiveness depends on variations in the potency of effector functions and kinetics of HIV protein expression, we developed a mathematical model describing CTL‐target cell interactions during successive infection cycles. The results show that substantially higher CTL‐mediated target cell elimination rates are required to achieve control as there is less time for CTL to act before infected cells release progeny virions. Furthermore, in vitro experiments with HIV recombinant viruses showed that the RT‐specific CTL were at least as effective as the Rev‐specific CTL, but only if the RT epitope was expressed as part of the early protein Nef. Together these results indicate that CTL control ongoing HIV reproduction more effectively if they are able to recognize infected cells earlier during individual viral replication cycles. This provides rationale for immunization strategies that aim at inducing, boosting or skewing CTL responses to early regulatory proteins in AIDS vaccine development.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 90%

Section: Inhibition Of Hiv Reproduction By Ctlmentioning

confidence: 99%

Section: Impact Of Epitope Expression Kinetics On Ctl Effectiveness In Vitromentioning

confidence: 99%

See 2 more Smart Citations

Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes

et al. 2002

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“…Recent evidence highlights the importance of the CTL responses against the proteins of HIV that are produced early during infection, in particular Tat and Rev, which are the only two viral proteins produced before Nef down-modulates MHC I expression [56]. Indeed, the selective pressure that CD8+ T cells exert on the virus, during the acute phase of the infection, pushes HIV to mutate in its immunodominant CTL epitopes faster and more frequently in the early proteins than in the late proteins [9,87], thus favoring immune escape and rapid establishment of chronic infection [20,32,45,69,88,89,95,96,116,169,218,235,236]. Mathematical models and in vitro studies suggest that CTL responses directed against HIV early proteins suppress virus production more effectively [96,218,221,235,236], and this is confirmed by studies in monkeys showing that CTL responses directed to Tat and Rev are more efficacious to control SIV replication than CTL responses against Gag and Pol [210].…”

Section: Tat Is Immunogenicmentioning

confidence: 99%

Recent Advances in the Development of HIV-1 Tat-Based Vaccines

Caputo¹,

Gavioli²,

Ensoli

2004

CHR

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Over the last two decades most of the efforts in HIV vaccine development have been based on the use of the HIV Env with the goal to induce sterilizing immunity. However, as a result of Env variability disappointing results have been obtained in preclinical and phase III clinical trials. Although the objective of a preventive immunity still remains a priority, secondary endpoints (e.g. block of virus replication and disease onset) are being considered at the present as more achievable end-points in HIV vaccine development. This is based on accumulating evidence indicating that low viral load correlates with maintenance of immune functions and slow progression to disease, and that cell-mediated immunity plays a major protective role in the absence of sterilizing immunity. The promising results obtained in non-human primates with a vaccine based on a native Tat protein (B-clade), which is an early regulatory protein key for HIV replication and AIDS pathogenesis, highlights the importance of targeting the virus very early after infection. In particular, the immune response against Tat appears to modify the virus-host interactions at the very beginning of infection, thus containing the depletion of critical immune cells and the progression of infection. Moreover, since Tat targets and induces maturation of dendritic cells, has immunomodulatory activities and drives Th-1 and CTL responses, immunization with Tat may drive or increase these immune responses also against other HIV antigens to support an effective, long-lasting and hopefully even sterilizing antiviral immunity. Finally, Tat B-clade is similarly recognized by sera from individuals infected by different virus clades (A, B, C, D) supporting the concept of a cross-clade vaccine. Therefore, the Tat-vaccine should contain virus replication protecting from disease progression (non-sterilizing immunity) or even favoring an abortive infection. Although only a phase III clinical trial will establish the efficacy of this vaccine strategy, the Tat-vaccine has recently entered preventive and therapeutic phase I clinical testing in Italy to establish safety (primary-end-point) and immunogenicity (secondary end-point) and phase II studies are being prepared.

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The advantage of early recognition of HIV-infected cells by cytotoxic T-lymphocytes

Gruters

Baalen

Osterhaus

2002

Vaccine

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Construction and characterisation of infectious recombinant HIV-1 clones containing CTL epitopes from structural proteins in Nef

Cited by 5 publications

References 30 publications

Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes

Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes

Recent Advances in the Development of HIV-1 Tat-Based Vaccines

The advantage of early recognition of HIV-infected cells by cytotoxic T-lymphocytes

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