Protection of rhesus macaques against disease progression from pathogenic SHIV-89.6PD by vaccination with phage-displayed HIV-1 epitopes

Abstract

The antigenic polymorphism of HIV-1 is a major obstacle in developing an effective vaccine. Accordingly, we screened random peptide libraries (RPLs) displayed on phage with antibodies from HIV-infected individuals and identified an array of HIV-specific epitopes that behave as antigenic mimics of conformational epitopes of gp120 and gp41 proteins. We report that the selected epitopes are shared by a collection of HIV-1 isolates of clades A-F. The phage-borne epitopes are immunogenic in rhesus macaques, where they elicit envelope-specific antibody responses. Upon intravenous challenge with 60 MID50 of pathogenic SHIV-89.6PD, all monkeys became infected; however, in contrast to the naive and mock-immunized monkeys, four of five mimotope-immunized monkeys experienced lower levels of peak viremia, followed by viral set points of undetectable or transient levels of viremia and a mild decline of CD4+ T cells, and were protected from progression to AIDS-like illness. These results provide a new approach to the design of broadly protective HIV-1 vaccines.

Control of Viremia and Prevention of Simian-Human Immunodeficiency Virus-Induced Disease in Rhesus Macaques Immunized with Recombinant Vaccinia Viruses plus Inactivated Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Particles

“…The four vaccinated animals used in the present study were protected against the rapid depletion of CD4 ϩ T cells and controlled postpeak viremia after challenge with the highly pathogenic SHIV DH12R-PS1 to low but detectable levels. This result is similar to those of several recently reported prime and boost studies in which immunized monkeys were challenged with a different highly pathogenic SHIV, SHIV 89.6P (2,7,8,18,65,74). In several of those experiments, potent antiviral cellular immune responses were measured both prior to and following SHIV 89.6P inoculation.…”

“…These include immunizations with plasmid DNAs and live viral vectors, used singly or in combination (2,8,14,21,24,32,41,65,69,74). While transient reductions in the postpeak viremia (virus set point) were achieved for some vaccinated macaques challenged with pathogenic SIV mac strains (33,55), more-impressive control of virus replication and prevention of the rapid and irreversible depletion of CD4 ϩ T cells have been obtained in studies that utilized the highly pathogenic SHIV 89.6P strain (2,7,8,18,65,74). However, the vaccine-elicited CTL responses only modestly reduced virus replication during the first 2 to 3 weeks of infection in both SIV-and SHIV-challenged animals and, in the case of the SIV-infected monkeys, failed to prevent the development of immunodeficiency in many of the vaccinees (1,10,33,45,55,56,60).…”

High Attenuation and Immunogenicity of a Simian Immunodeficiency Virus Expressing a Proteolysis-resistant Inhibitor of NF-κB

“…Viral infection was performed by intravenous inoculation of 100 TCID 50 of viral stocks. The infected monkeys were monitored for plasma viral load by detecting SIV RNA using a real-time reverse transcription-PCR with a threshold sensitivity of 200 viral RNA copies Eq/ml (31). The gag region was amplified by using the following primers and probe: SIV-F, 5Ј-AGTATGGGCAGCAAATGAAT-3Ј; SIV-R, 5Ј-TTCTCTTCTGCGTGAATGC-3Ј; SIV-P, 6FAM-AGATTTGGATTAG-CAGAAAGCCTGTTGGA-TAMRA.…”

Predicting the Impact of a Nonsterilizing Vaccine against Human Immunodeficiency Virus

“…We then asked whether a vaccine that reduces the viral load by Ͻ0.5 log 10 copies ml Ϫ1 could reduce HIV incidence and mortality if it were accompanied by a significant reduction in disease progression. This question is interesting because it is currently unclear whether the reduced viral load seen when vaccinated monkeys are infected is stable or increases slowly (1,11,22,51). The model was thus used to consider the effects of a progression-slowing vaccine that had a minimal effect on viral load (reducing viral loads by only 0.1 to 0.5 log 10 copies ml Ϫ1 ) but a significant effect on reducing the disease progression rate (p V is 0 to 80% of the normal rate).…”

“…Thus far, both therapeutic and sterilizing vaccination strategies for HIV have proved elusive (35). However, recent studies in primates suggest that it is possible to produce disease-modifying vaccines that significantly reduce viral loads and AIDS mortality (1,11,22,51). These vaccines appear to work primarily by inducing cytotoxic T lymphocyte (CTL) immunity.…”