Immune response of rhesus macaques to recombinant simian immunodeficiency virus gp130 does not protect from challenge infection

212

An experimental vaccine consisting of five DNA plasmids expressing different combinations and forms of simian immunodeficiency virus-macaque (SIVmac) proteins has been evaluated for the ability to protect against a highly pathogenic uncloned SIVmac251 challenge. One vaccine plasmid encoded nonreplicating SIVmac239 virus particles. The other four plasmids encoded secreted forms of the envelope glycoproteins of two T-cell-tropic relatives (SIVmac239 and SIVmac251) and one monocyte/macrophage-tropic relative (SIV-mac316) of the uncloned challenge virus. Rhesus macaques were inoculated with DNA at 1 and 3, 11 and 13, and 21 and 23 weeks. Four macaques were inoculated intravenously, intramuscularly, and by gene gun inoculations. Three received only gene gun inoculations. Two control monkeys were inoculated with control plasmids by all three routes of inoculation. Neutralizing antibody titers of 1:216 to 1:768 were present in all of the vaccinated monkeys after the second cluster of inoculations. These titers were transient, were not boosted by the third cluster of inoculations, and had fallen to 1:24 to 1:72 by the time of challenge. Cytotoxic T-cell activity for Env was also raised in all of the vaccinated animals. The temporal appearance of cytotoxic T cells was similar to that of antibody. However, while antibody responses fell with time, cytotoxic T-cell responses persisted. The SIVmac251 challenge was administered intravenously at 2 weeks following the last immunization. The DNA immunizations did not prevent infection or protect against CD4 ؉ cell loss. Long-term chronic levels of infection were similar in the vaccinated and control animals, with 1 in 10,000 to 1 in 100,000 peripheral blood cells carrying infectious virus. However, viral loads were reduced to the chronic level over a shorter period of time in the vaccinated groups (6 weeks) than in the control group (12 weeks). Thus, the DNA vaccine raised both neutralizing antibody and cytotoxic T-lymphocyte responses and provided some attenuation of the acute phase of infection, but it did not prevent the loss of CD4 ؉ cells.

Section: Discussionmentioning

confidence: 94%

Simian immunodeficiency virus DNA vaccine trial in macaques

Arthos

Montefiori

et al. 1996

212

“…Trials in rhesus monkeys have shown that vaccine protection against SIVmac239 and SIVmac251 is very difficult to achieve even under idealized laboratory conditions. Vaccine trials that have used inactivated whole virus, envelope protein, vaccinia virus recombinants, multivalent vaccinia virus recombinants, and multivalent vaccinia virus recombinants followed by particle boosting have shown little or no protection against challenge by these viruses (7,10,22,26,30,31). These vaccine failures have occurred despite extensive attempts to match the strain of challenge virus closely to the vaccine and to time the challenge at or near the peak of vaccine-induced immune responses.…”

mentioning

confidence: 99%

Identification of Highly Attenuated Mutants of Simian Immunodeficiency Virus

Desrosiers

Lifson

Gibbs

et al. 1998

212

Deletion mutants of the pathogenic clone of simian immunodeficiency virus isolate 239 (SIVmac239) were derived that are missingnef, vpr, and upstream sequences (US) in the U3 region of the LTR (SIVmac239Δ3), nef, vpx, and US (SIVmac239Δ3x), and nef, vpr,vpx, and US (SIVmac239Δ4). These multiply deleted derivatives replicated well in the continuously growing CEMx174 cell line and were infectious for rhesus monkeys. However, on the basis of virus load measurements, strength of antibody responses, and lack of disease progression, these mutants were highly attenuated. Measurements of cell-associated viral load agreed well with assays of plasma viral RNA load and with the strengths of the antibody responses; thus, these measurements likely reflected the extent of viral replication in vivo. A derivative of SIVmac239 lacking vif sequences (SIVmac239Δvif) could be consistently grown only in avif-complementing cell line. This Δvif virus appeared to be very weakly infectious for rhesus monkeys on the basis of sensitive antibody tests only. The weak antibody responses elicited by SIVmac239Δvif were apparently in response to low levels of replicating virus since they were not elicited by heat-inactivated virus and the anti-SIV antibody responses persisted for greater than 1 year. These results, and the results of previous studies, allow a rank ordering of the relative virulence of nine mutant strains of SIVmac according to the following order: Δvpr > Δvpx > ΔvprΔvpx ≅ Δnef > Δ3 > Δ3x ≥ Δ4 > Δvif > Δ5. The results also demonstrate that almost any desired level of attenuation can be achieved, ranging from still pathogenic in a significant proportion of animals (Δvpr and Δvpx) to not detectably infectious (Δ5), simply by varying the number and location of deletions in these five loci.

“…Unfortunately, vaccines consisting of inactivated virus particles, purified viral proteins, or replication-competent vectors expressing HIV or simian immunodeficiency virus (SIV) proteins have not consistently fulfilled these requirements in either the HIV-1/chimpanzee or the SIV/macaque monkey model system. In many cases, immunization with such vaccines failed to generate significant protection even though strong antiviral immune responses could be detected (4,9,11,19,39,43,47,53,54,57). In successful vaccination experiments, the absence of detectable challenge virus (5,15,17,22,23,26,27,29,42) or significant reduction of challenge virus loads or delays in the onset of immunodeficiency (2,7,13,21,24,25,28,36,48) has been reported.…”

mentioning

confidence: 99%

Live, attenuated simian immunodeficiency virus vaccines elicit potent resistance against a challenge with a human immunodeficiency virus type 1 chimeric virus

Shibata

Siemon

Czajak

et al. 1997

106

Three rhesus macaques, previously immunized with SIV⌬3 or SIV⌬2, each an attenuated derivative of SIV mac239 , and two naive monkeys were challenged with 30,000 50% tissue culture infective doses of SHIV, an SIV/human immunodeficiency virus type 1 (HIV-1) chimeric virus bearing the dual-tropic envelope of HIV-1 DH12. By several criteria, including virus isolation, serological assays, and PCR (both DNA and reverse transcriptase), SHIV levels were reduced to barely detectable levels in the circulating blood of vaccinated animals. The resistant SIV-vaccinated macaques had no preexisting neutralizing antibodies directed against SHIV, nor did they produce neutralizing antibodies at any time over a 14-month observation period following SHIV challenge. Interestingly, SIV sequences, derived from the vaccine, could be amplified from numerous tissue samples collected at the conclusion of the experiment, 60 weeks postchallenge, but SHIV-specific sequences (viz., HIV-1 env) could not. These results demonstrate that live attenuated SIV vaccines provide strong long-term protection even against challenge strains with highly divergent envelope sequences.