These domains have been shown to regulate protein-protein interactions. Thus, this amino acid change may cause alterations in protein-protein interactions that are either quantitatively or qualitatively different than those seen with the parental vaccine virus. This study provided a good opportunity to examine the role of neutralizing antibodies in protection against challenge virus.
These antibodies appeared after challenge. These increased after challenge. Therefore, neutralizing antibodies appeared to play a minimal role in controlling the initial burst of SHIV KU replication.
It is also of interest that all animals displayed significantly different neutralization titers to SHIV KU and VII, despite the fact that the gp sequences of these viruses are closely related.
It is possible that one or more amino acid substitutions directly altered a major neutralization epitope s resulting in the change in neutralization titer. As discussed above, glycosylation has been shown to play an important role in the conformation of this protein and thus may be responsible for the difference in neutralization titer. Although we do not have prechallenge CTL data on these animals, other animals immunized in an identical manner with this vaccine developed CTLs against proteins of this challenge virus within 6 months of immunization.
These CTLs have persisted for more than 1 year A. Kumar et al. In addition, the longest-surviving control animal in this study was the only macaque to produce cell-mediated immune responses against the challenge virus. Taken together, these two lines of evidence suggest that CTLs have played a major role in suppressing virus replication and perhaps in the progressive elimination of infected cells.
Our data are in agreement with other data that suggest a role for CTLs in the control of HIV replication in humans 2 , 18 , 19 and SIV replication in macaques 12 , 13 , In all six animals, CTLs were directed against the envelope as well as the core proteins of the virus. Although we did not find any distinctive bias regarding the induction of CTLs to individual proteins, Gag-specific CTL activity was higher than that induced to Env or Pol.
We also did not find any difference in the immune responses between the animals from which virus was recovered from lymph node i. This study demonstrated that the immunized animals have maintained high levels of humoral and cell-mediated immune responses despite the lack of detectable replication in PBMC and a lack of detectable viral RNA in plasma.
However, these immune responses correlated with the persistence of viral DNA derived from vaccine virus. This DNA could represent a reservoir of latent virus that is capable of sporadic reactivation. Reactivation from this viral reservoir could provide the persistent source of antigen that is thought to be necessary for the maintenance of high levels of immune responses.
This study also demonstrated that, although both V-DNA and the immune responses to vaccine virus were persistent, there must have been a substantial decline in the level of V-DNA.
In animals PEy and PWl, this decrease occurred despite the reduction in effectiveness of the immune response to the newly isolated variants compared to the response to the parental vaccine viruses. This raises the possibility that mechanisms other than the cellular and humoral immune responses may have been responsible for the maintenance of low viral loads of the vaccine virus.
This alternate mechanism of virus control might include soluble factors that have been shown to be inhibitory to virus replication 1 , 4 , 21 , Alternatively, although the effectiveness of the immune responses to the new variants is reduced, they may be sufficiently potent to inhibit the replication of a virus that is already attenuated. We thank Fenglan Jia for excellent technical assistance. Panicali and G. Mazzara, Therion Biologics, Cambridge, Mass. Read article at publisher's site DOI : J Neuroimmune Pharmacol , 5 1 , 16 Dec Review Free to read.
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Go to:. Virus recovery from lymph nodes. Amplification of gp and nef sequences for sequencing. Lymphocyte proliferation assay. Generation of bulk CTL population and chromium release assay. Serum neutralization assay. Nucleotide sequence accession numbers. Open in a separate window. NR, no virus could be recovered at week TABLE 3 Proliferative T-cell responses to vaccine and challenge viral antigens in macaques at various times following challenge.
The Env, Gag, and Pol specific lysis values were determined by infecting herpesvirus papio-transformed B-LCL with recombinant vaccinia virus expressing one of these proteins and then using these cells as targets in a 4-h chromium release assay.
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