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Wednesday, 1:30 - 3:30 pm
Background: Aldrithiol-2 (AT-2) inactivates retroviral infectivity by selective covalent modification of Cys on internal viral proteins, while preserving the structure and function of viral envelope glycoproteins, in which Cys are disulfide bonded. Potential advantages of AT-2-inactivated virions as vaccine immunogens include display of neutralizing epitopes in native trimeric form, and uptake and cross presentation by dendritic cells (DC).
METHODS: To evaluate AT-2-inactivated SIV (AT-2 SIV) in a therapeutic vaccination study, Indian rhesus macaques were infected with SIVmac239. Antiretroviral treatment (ART; PMPA and FTC) was initiated in 14 of 16 animals 10 weeks post-inoculation (2 controls were untreated). At 16 weeks on ART (26 weeks post-inoculation) treated animals were assigned to receive either continued ART only, or continued ART and vaccination; animals with comparable viral load profiles were assigned to each group. Vaccination (weeks 26 and 32 post-inoculation) consisted of 10 m g (total p28CA equivalent) AT-2 SIV intramuscularly and intradermally, adjuvanted with 3.5 mg of a CpG-motif-containing oligonucleotide. Vaccinees also received 2 X 106 autologous in vitro matured monocyte-derived DC, pulsed ex vivo with AT-2 SIV (2 mg p28 CA equivalent, subcutaneously). Immune responses were monitored with an AT-2 SIV-stimulated PBMC IFN-g ELISpot assay. ART was discontinued 4 weeks after the second immunization.
Results: ART resulted in decreased plasma viremia (8/14 to <20 copies/mL). Treated animals that did not suppress plasma viremia to <50 copies/mL showed high pre-ART viral load and an RT mutation associated with in vitro resistance to PMPA (K65R). Treated animals showed transient increases in cellular immune responses associated with declining viremia after starting ART. Vaccinees showed increased ELISpot responses after vaccination. After stopping ART, most animals, including vaccinees, showed rebound viremia to within 10-fold of pre-ART levels. The only animal showing sustained post-ART control of plasma viremia (pre-ART (weeks 7 to 10 post-inoculation) 1.9 X 106 copies/mL vs 8.8 X 103copies/mL, weeks 16 to 20 off ART) maintained measurable ELISpot responses despite dropping viral load on ART, and showed strong ELISpot responses to vaccination.
Conclusions: Incompletely effective ART limits interpretation of vaccine efficacy in this initial study. Follow-up studies will focus on use of more effective ART regimens and characterization of immune responses associated with off-ART control of viremia.
Keywords: SIV; AT-2; therapeutic vaccination