Macaques infected long-term with attenuated simian immunodeficiency virus (SIVmac) remain resistant to wild-type challenge, despite declining cytotoxic T lymphocyte responses to an immunodominant epitope

A highly effective attenuated equine infectious anemia virus (EIAV) vaccine (EIAV D9)). An inverse correlation between challenge strain Env variation and vaccine protection from disease was observed. Given the striking differences in protective immunity, we hypothesized that analysis of the humoral and cellular immune responses to the Env protein could reveal potential determinants of vaccine protection. Neutralization activity against the homologous Env or challenge strain-specific Env in immune sera from the vaccinated ponies did not correlate with protection from disease. Cellular analysis with Env peptide pools did not reveal an association with vaccine protection from disease. However, when individual vaccinespecific Env peptides were utilized, eight cytotoxic-T-lymphocyte (CTL) peptides were found to associate closely with vaccine protection. One of these peptides also yielded the only lymphoproliferative response associated with protective immunity. The identified peptides spanned both variable and conserved regions of gp90. Amino acid divergence within the principal neutralization domain and the identified peptides profoundly affected immune recognition, as illustrated by the inability to detect cross-reactive neutralizing antibodies and the observation that certain peptide-specific CTL responses were altered. In addition to identifying potential Env determinants of EIAV vaccine efficacy and demonstrating the profound effects of defined Env variation on immune recognition, these data also illustrate the sensitivity offered by individual peptides compared to peptide pools in measuring cellular immune responses in lentiviral vaccine trials.Equine infectious anemia virus (EIAV) is a macrophagetropic equine lentivirus that has been used extensively as a model for human immunodeficiency virus type 1 (HIV-1) persistence and pathogenesis and for AIDS vaccine development (8,18,24,25,29,36,(48)(49)(50)55). Compared to other progressively degenerative lentiviral infections, EIAV is characterized by three distinct phases of infection, namely, acute, chronic, and inapparent. By 2 months post-EIAV exposure, most horses experience an acute disease episode characterized by high fever, a drop in platelets, and a high viral load. The horse then enters a chronic stage of infection characterized by recurrent disease episodes, which typically progress to the inapparent carrier stage of disease for the life span of the animal (48). During the inapparent phase, the horse has gained immunologic control of the virulent and constantly evolving lentivirus, as demonstrated by the fact that whole blood transfers from inapparent carriers to naïve horses can cause an acute episode within 2 months (31,43,48). Additionally, if the inapparent carrier is immunosuppressed or stressed, there can be recrudescing disease associated with a new viral quasispecies. Inapparent carriers of EIAV appear to be resistant to additional exposure to EIAV variant strains, indicating that the horse has gained a high level of prophylactic immunity (48). Th...

Section: Discussionmentioning

confidence: 99%

Envelope Determinants of Equine Infectious Anemia Virus Vaccine Protection and the Effects of Sequence Variation on Immune Recognition

Tagmyer

Craigo

Cook

et al. 2008

“…If cell-mediated immune responses are the mechanism of protection in live attenuated SIV vaccinees, then a characteristic expansion of memory CD8 ϩ CTL and immune activation should be detected following virus challenge (17,19). Yet evidence for immune activation or expansion of SIV-specific CTL responses following rechallenge has not been reported (44,50). Even where protection against superinfection is incomplete, vaccine-mediated control of virus replication occurs before detection or expansion of CD8 ϩ SIV-specific CTL responses (1,51).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, an inverse correlation has been reported between the precursor frequency of SIV-specific CD8 ϩ CTL responses elicited by certain vaccine approaches and virus load following challenge (20,55). Although several groups have reported a correlation between SIV-specific CD8 ϩ CTL responses in live attenuated SIV vaccinees and protection against superinfection with wild-type SIV (24)(25)(26)56), other groups have failed to corroborate such observations and dispute a role for SIVspecific CD8 ϩ CTL in mediating protection (1,32,44,50,52).…”

mentioning

confidence: 99%

CD8 ⁺ Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus

Stebbings¹,

Berry²,

Waldmann

et al. 2005

Self Cite

In order to test the hypothesis that CD8 ؉ cytotoxic T lymphocytes mediate protection against acute superinfection, we depleted >99% of CD8 ؉ lymphocytes in live attenuated simian immunodeficiency virus macC8 (SIVmacC8) vaccinees from the onset of vaccination, maintained that depletion for 20 days, and then challenged with pathogenic, wild-type SIVmacJ5. Vaccinees received 5 mg per kg of humanized anti-CD8 monoclonal antibody (MAb) 1 h before inoculation, followed by the same dose again on days 3, 7, 10, 13, and 17. On day 13, peripheral CD8 ؉ T lymphocytes were >99% depleted in three out of four anti-CD8 MAb-treated vaccinees. At this time attenuated SIVmacC8 viral RNA loads in anti-CD8 MAb-treated vaccinees were significantly higher than control vaccinees treated contemporaneously with nonspecific human immunoglobulin. Lymphoid tissue CD8 ؉ T lymphocyte depletion was >99% in three out of four anti-CD8 MAb-treated vaccinees on the day of wild-type SIVmacJ5 challenge. All four control vaccinees and three out of four anti-CD8 MAb-treated vaccinees were protected against detectable superinfection with wild-type SIVmacJ5. Although superinfection with wild-type SIVmacJ5 was detected at postmortem in a single anti-CD8 MAb-treated vaccinee, this did not correlate with the degree of preceding CD8 ؉ T lymphocyte depletion. Clearance of attenuated SIVmacC8 viremia coincided with recovery of normal CD8 ؉ T lymphocyte counts between days 48 and 76. These results support the view that cytotoxic T lymphocytes are important for host-mediated control of SIV primary viremia but do not indicate a central role in protection against acute superinfection conferred by inoculation with live attenuated SIV.

“…Prime-boost SIV vaccine regimens with plasmid DNA and viral vectors induce robust anamnestic T-cell responses following pathogenic SIVmac challenge, including cytotoxic T lymphocytes, although control of viral replication is inconsistent (15,22,32,53). However, monkeys vaccinated with live, attenuated SIV do not produce a strong anamnestic T-cell response following pathogenic-virus challenge (1,25,40,48). There are three nonexclusive mechanisms that could account for the difference in the vaccine-induced T-cell responses in monkeys vaccinated with live, attenuated SIV or SHIV and those vaccinated with prime-boost strategies.…”

Section: Cd8mentioning

confidence: 99%

With Minimal Systemic T-Cell Expansion, CD8⁺T Cells Mediate Protection of Rhesus Macaques Immunized with Attenuated Simian-Human Immunodeficiency Virus SHIV89.6 from Vaginal Challenge with Simian Immunodeficiency Virus

Genescà

Skinner

Hong

et al. 2008

The presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (SHIV89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here, we definitively demonstrate the protective role of the SIV-specific CD8؉ T-cell response in SHIV-immunized monkeys by CD8؉ lymphocyte depletion, an intervention that abrogated SHIVmediated control of challenge virus replication and largely eliminated the SIV-specific T-cell responses in blood, lymph nodes, and genital mucosa. While in the T-cell-intact SHIV-immunized animals, polyfunctional and degranulating SIV-specific CD8 ؉ T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 postchallenge, strikingly, expansion of SIV-specific CD8 ؉ T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV89.6 is primarily mediated by CD8 ؉ T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effectorcytotoxic CD8 ؉ T cells can provide significant protection from vaginal SIV challenge.