advanced search

<< Back To Home

NEW THIS FRIDAY: TWO ON SIV VACCINE IN MONKEYS

Wednesday, 11th of September 2013

• TWO ON SIV VACCINE IN MONKEYS
  
• VACCINE CLEARS HIV-LIKE VIRUS IN MONKEYS

By Rebecca Morelle Science reporter, BBC World Service

The team looked at a form of SIV that is up to 100 times more deadly than HIV

A vaccine for the monkey equivalent of HIV appears to eradicate the virus, a study suggests.

Research published in the journal Nature has shown that vaccinated monkeys can clear Simian Immunodeficiency Virus (SIV) infection from their bodies.

It was effective in nine of the 16 monkeys that were inoculated.

The US scientists say they now want to use a similar approach to test a vaccine for HIV in humans.

Prof Louis Picker, from the Vaccine and Gene Therapy Institute at Oregon Health and Science University, said: "Its always tough to claim eradication - there could always be a cell which we didnt analyse that has the virus in it. But for the most part, with very stringent criteria... there was no virus left in the body of these monkeys."

Search and destroy

The research team looked at an aggressive form of virus called SIVmac239, which is up to 100 times more deadly than HIV.

Infected monkeys usually die within two years, but in some inoculated primates the virus did not take hold.

It maintains an armed force, that patrols all the tissues of the body, all the time, indefinitely”

End Quote Prof Louis Picker Oregon Health and Science University

The vaccine is based on another virus called cytomegalovirus (CMV), which belongs to the herpes family.

It used the infectious power of CMV to sweep throughout the body. But instead of causing disease, it has been modified to spur the immune system into action to fight off the SIV molecules.

"It maintains an armed force, that patrols all the tissues of the body, all the time, indefinitely," explained Prof Picker.

The researchers gave rhesus macaque monkeys the vaccine, and then exposed them to SIV.

They found that at first the infection began to establish and spread. But then the monkeys bodies started to respond, searching out and destroying all signs of the virus.

Of the monkeys that successfully responded to the vaccine, they were still clear of infection between one-and-a-half and three years later.

Prof Picker said his team was still trying to work out why the vaccination worked in only about half of the monkeys.

"It could be the fact that SIV is so pathogenic that this is the best you are ever going to get.

"There is a battle going on, and half the time the vaccine wins and half the time it doesnt," he said.

Human trials

The researchers are now testing the vaccine to see if it can be used after SIV exposure to treat and potentially cure infected monkeys.

They also want to see if the technique could work in humans.

Prof Picker said: "In order to make a human version we have to make sure it is absolutely safe.

The researchers now want to move from monkeys to test the vaccine in humans

"We have now engineered a CMV virus which generates the same immune response but has been attenuated [modified to lose its virulence] to the point where we think it is unequivocally safe."

This would first have to pass through the regulatory authorities, but if it does, he said he hoped to start the first clinical trials in humans in the next two years.

Commenting on the research, Dr Andrew Freedman, from Cardiff University School of Medicine, said: "This suggests that prophylactic vaccines - vaccines designed to prevent infection - using CMV vectors may be a promising approach for HIV.

"While they may not prevent the initial infection, they might lead to subsequent clearance, rather than the establishment of chronic infection."

 

• IMMUNE CLEARANCE OF HIGHLY PATHOGENIC SIV INFECTION

Scott G. Hansen,1, 4 Michael Piatak Jr,2, 4 Abigail B. Ventura,1 Colette M. Hughes,1 Roxanne M. Gilbride,1 Julia C. Ford,1 Kelli Oswald,2 Rebecca Shoemaker,2

Yuan Li,2 Matthew S. Lewis,1 Awbrey N. Gilliam,1 Guangwu Xu,1 Nathan Whizin,1 Benjamin J. Burwitz,1  Shannon L. Planer,1 John M. Turner,1 Alfred W. Legasse,1

Michael K. Axthelm,1 Jay A. Nelson,1 Klaus Früh,1 Jonah B. Sacha,1 Jacob D. Estes,2 Brandon F. Keele,2 Paul T. Edlefsen,3 Jeffrey D. Lifson2 & Louis J. Picker1 et al.

Nature (2013)

Received

01 May 2013

Accepted 01 August 2013

Published online11 September 2013

For full access, go to http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12519.html

Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections1, 2, 3, 4. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69–172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.

At a glance

Figures

First | 1-2 of 3 | Last

left

Figure 1: Virological analysis of early RhCMV/SIV vector-mediated protection.

a, Plasma viral load (measured as log(copy equiv. per ml)) profiles of five RhCMV/SIV vector-vaccinated RM with complete control of viraemia after intrarectal SIVmac239 challenge. All five RM controlled viraemia to below the 30 copy equiv. ml−1 limit of quantification for the standard plasma viral load assay used for all pre-necropsy samples, and to below the 1–5 copy equiv. ml−1 limit of detection for the ultrasensitive plasma viral load assay used on necropsy samples (individual detection limits for each terminal sample shown). b, Frequencies of peripheral blood memory CD8+ T cells specific for SIV proteins that were (Gag plus Pol) or were not (Vif) included in the RhCMV/SIV vectors, shown before and after the onset of the controlled SIV infection. The response frequencies (mean ± s.e.m.) were normalized to the response frequencies immediately before SIV infection for the vaccine-elicited SIV Gag- and Pol-specific responses, and to the peak frequencies after SIV infection for the de novo SIV Vif-specific responses. c, Analysis of tissue-associated SIV DNA and RNA (copy equiv. per 108 cell equiv.) in the five RhCMV/SIV vector-protected RM at necropsy using ultrasensitive quantitative PCR and RT–PCR. BM, bone marrow; LN, lymph nodes; PID, post-infection day; SIM, small intestine mucosa.

Figure 2: Longitudinal analysis of RhCMV/SIV vector-mediated protection after intravaginal challenge.

a, Plasma viral load (measured as log(copy equiv. per ml)) profiles of groups A (RhCMV/SIV vector-vaccinated), B (control RhCMV vector-vaccinated) and C (unvaccinated) RM after infection by repeated, limiting dose, intravaginal SIVmac239 challenge, with the day of infection defined as the challenge before the first above-threshold plasma viral load. The fraction of infected RM that met controller criteria (see Methods) in group A (9 out of 16) versus groups B and C (0 out of 18) was significantly different (P = 0.0002) by two-sided Fishers exact test. Note that Rh20363 initially manifested aviraemic protection, but then relapsed with productive, albeit controlled, infection at week 31 after infection. b, Mean (and s.e.m.) frequencies of peripheral blood memory CD8+ T cells specific for SIV proteins that were (Gag plus Pol) or were not (Vif) included in the RhCMV/SIV vectors, measured before and after the onset of SIV infection in the nine group A RM with initial aviraemic control (response frequencies normalized as described in Fig. 1b). Asterisks indicate n = 8 (minus Rh20363 post-relapse); daggers indicate n = 7 (minus Rh20363 and Rh20347, the latter used in the CD8+ cell depletion study described in Supplementary Fig. 14). c, Quantification of tissue-associated SIV RNA (left) and DNA (right) (copies per 108 cell equiv.) in the designated longitudinal samples of the nine group A controllers versus two representative viraemic progressors. All sample types were analysed at weeks 5, 9 and 17 in all RM. All sample types were analysed a fourth time in all controller RM between post-infection weeks 30 and 40, and PBMCs, bone marrow and lymph node samples were analysed a fifth time in eight out of nine controller RM between post-infection weeks 42 and 55. Each symbol represents a single determination from the designated tissue, except when a multiplication factor is shown (for example, ×7 indicates a total of seven samples from different RM with below threshold measurements for that time point).

Figure 3: Virological analysis of medium- to long-term RhCMV/SIV vector-mediated protection.

a, b, Plasma viral load (measured as log(copy equiv. per ml)) profiles of ten RhCMV/SIV vector-vaccinated RM that controlled SIV infection after intrarectal challenge (eight long term (a) and two medium term (b)). The limit of detection for all pre-terminal plasma viral load assays is 30 copy equiv. ml−1; the limit of detection for the ultrasensitive assay used on the terminal sample of the study was ≤1 copy equiv. ml−1. Note that one of the RM with medium-term protection (Rh26467) was CD8+ lymphocyte-depleted 10 days before the terminal sample. c, d, Quantification of tissue-associated SIV DNA and RNA in four long-term and two medium-term protected RhCMV/SIV-vaccinated RM studied at necropsy, including the CD8+ cell-depleted RM (Rh26467). e, Assessment of residual replication-competent, cell-associated SIV in medium- and long-term protected RM by adoptive transfer of 6 × 107 haematolymphoid cells (3 × 107 blood leukocytes and 3 × 107 lymph node cells or, in one transfer from Rh26467, represented by the open symbol, 3 × 107 bone marrow leukocytes and 3 × 107 spleen cells) to SIV-naive RM with SIV infection in the recipient RM delineated by plasma viral load. Cell transfers from RM with conventional elite SIV control and ART-suppressed SIV infection resulted in rapid onset of SIV infection in the recipient RM, but no SIV infection was observed in RM receiving cells from medium- to long-term RhCMV/SIV vector-protected RM (including Rh26467, analysed both before and after CD8+ cell depletion).