Aphase two clinical thera- peutic trial of a human immunodeficiency virus (HIV-1) vaccine, based on the transactivator of transcription (TAT) protein found in most infected individuals, will begin in South Africa in the second half of 2011.
The therapeutic trial is sponsored by the South African Department of Health and the Italian National Institute of Health (ISS), which conducted the preclinical trials and the phase one preventive and thera- peutic trials in humans of the vaccine and is concluding the phase two clinical trials of the vaccine in Italy. The University of Limpopo will conduct the trial at its Medical University of Southern Africa campus, in Rosslyn, Pretoria.
The research is aimed at reducing the immune activation found in HIV-1-infected individuals on antiretroviral (ARV) medication, says ISS National Aids Centre director Professor Barbara Ensoli.
“Even in successfully treated HIV-positive individuals, which means that they have a very low, or suppressed, viral load, ARV treatment is associated with strong immune activation in the individual. This leads to many new disorders arising in ARV-treated people, such as liver, kidney, central nervous system and cardiovascular diseases, as well as leading to new types of tumours and premature ageing found in immune activated hosts,” she says.
“The first aim of the trial is to determine if the vaccine is immu- nogenic (improves the immune system function) in the South African population and is able to induce a specific immune response.”
The trials will be used to determine if the immune activation can be reduced by vaccinating people already on ARV treatment, which will then determine if the vaccine is effective in improving the immune system functioning in individuals. If so, the amount of medication that HIV-positive people must take, and their associated side effects, could be reduced while improving their immune system functioning.
The vaccine underwent successful preclinical and phase one clinical trials in Italy. The phase two clinical trial is being concluded in Italy and interim results from this trial were published in the medical journal PlosOne, in December 2010.
The phase one and interim phase two results indicate that the vaccine is safe and immunogenic. Further, the immunological differences and abnormalities, which persist in ARV-treated individuals, can be reduced through administration of the vaccine.
The phase two therapeutic trials in South Africa will determine if this is true in the South African population, which predominantly suffers from HIV-1 subtype C, compared with Italy which predominantly has the subtype B viral strain, she says.
Why the TAT Protein?
The TAT protein, which plays a central role in the copying of HI viral ribonucleic acid into a host cell’s deoxyribonucleic acid, enabling the virus to replicate, is a regulatory protein that has a central role in HIV infection, virus replication, transmission from cell to cell in individuals and progression of the disease.
Further, the TAT protein has more conserved parts (mean- ing that these parts change little over the progression of the disease, between different strains of the disease and between different individual hosts of the disease) and enables scientists to target it for HIV treatment or control.
“We have found that the TAT protein plays a role in the chronic activation of the immune system, which we see in HIV infection. So, by blocking the TAT protein, we can potentially block the immune activation seen in HIV-infected individuals. This is what we have seen in phase two trials in Italy and hope to demonstrate in South Africa,” Ensoli says.
“TAT protein antibodies are seen only in a small fraction, about 20%, of infected individuals and are also seen in those who are asymptomatic. This is one of the reasons we wanted to target TAT, and is the ration- ale for our studies, because any effective treatments arising from these studies should be applicable to a broad range of HI viral strains.”
Most HIV vaccine studies have focused on the virus’s protein envelope but, because this envelope changes between different strains and hosts, the studies have failed to produce a broadly applicable vaccine for the virus. However, this did lead scientists to better understand the virus and how it interacts with a host’s immune system, she notes.
The study will vaccinate individuals who do not have TAT antibodies to determine if these antibodies can be induced, and whether a cellular immune response to TAT can be induced.
“This does not mean that, in the future, we will not vaccinate people who have TAT antibod- ies, for example, if they have low levels of TAT antibodies, because we would also like to measure what effect these antibodies will have on the progression of the disease,” she says.
“This is advanced research and we want to prove and get the data we recorded in Italy from this different setting and different virus,” she concludes.