S.01. HIV-1 Vaccine: where we were, where we are and where we will be?

Human immunodeficiency virus (HIV) has already infected more than 65 million individuals worldwide with 14,000 new infections taking place per day. In India alone, an estimated 5.1 million people have been infected with the virus since its first report in 1986. 89% of infected individuals are between 15–45 yuears ago group. The epidemic is taking serious turn in all southern states (except Kerala) where the prevalence rate in women attending antenatal clinics is more than 2%.

Although new antiretroviral drugs have been able to prolong the life of HIV infected individuals, the high cost of such therapy put it out of reach for most of the world. In addition, these drugs are partially successful because of side effects associated with prolonged use and the development of viral resistance to these drugs. Therefore, a safe and effective HIV preventive vaccine is urgently needed to bring the HIV/AIDS epidemic under control.

On the basis of phylogenetic analysis of sequence data of envelope gene, HIV-1 has been divided into 3 groups: M (Major), O (outlier) and N (non-M/non-O). The M group viruses are responsible for majority of infections worldwide. It comprises several different genetically associated but distinct viruses referred to as subtypes or clades A to D, F to H, J and K. These subtypes show geographic predilection. Subtype B is more prevalent in North America, Western Europe, Australia and Japan. Subtype C is the predominant virus in India, South Africa and other nations in southern Africa, Nepal and Southern China. At present more than 50% of HIV-1 infections worldwide are caused by subtype C virus strains. In India it accounts for more than 95% of HIV-1 infections.

Therefore, it is imperative that a vaccine based on the local circulating subtype should be designed and tested for immunogenicity in mice and non-human primate models. Since the plan is to use multi-gene vaccination strategy in which both envelope and gag-protease gene constructs will be used together in humans, envelope (glp 20) gene and gag protease gene of Indian HIV-1 subtype C virus were cloned in the mammalian expression plasmid DNA vector as well as in a virus vector, MVA (Modified Vaccinia Ankara). These gene constructs (two containing gpl 20 genes and one with gag-protease gene) were then evaluated for immunogenicity in mice and in bonnet monkeys in ‘prime-boost strategy format’ in which priming was done with DNA vaccine constructs and boosting was done with modified MVA constructs four weeks after priming. This strategy was found to be highly immunogenic both in mice and in bonnet monkeys. Immunized animals developed strong HIV-1 subtype C-specific and non-subtype C reactive immune responses (humoral as well as cell mediated immune responses). Humoral immune response was evaluated by ELISA. Cellular immune response was assayed by Cytotoxicity assay, ELISPOT assay and Lymphoproliferative assay. Interestingly, the memory of the immune response was detected even beyond 6 months in mice and beyond 10 months in monkeys. Immunized monkeys showed a very strong HIV-1 subtype C specific recall immune response when challenged with MVA constructs 46 weeks after vaccination with two doses of DNA vaccine.

The vaccine constructs are now slated for human trials in 2005. However before that, as a mandatory prerequisite for human trials, these constructs will under go preclinical toxicity testing in animals, which may be completed in 2004.

This work on the development of Indian HIV-1 subtype C DNA vaccine candidate has been undertaken at the National HIV Reference Centre in the Department of Microbiology, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi, under the Prime Minister's Jain Vigyan Mission Program since 1999. The Department of Biotechnology, Ministry of Science and Technology, Government of India funded this programme.