Azam Bolhassani

By Azam Bolhassani and Sima Rafati

Part of the book: Non-Viral Gene Therapy

By Azam Bolhassani and Tayebeh Saleh

Part of the book: Novel Gene Therapy Approaches

By Azam Bolhassani

Vaccination is one of the most successful approaches for controlling various viral diseases. Novel approaches will be needed to develop highly effective vaccines to prevent infectious diseases such as HIV. There are many aspects of HIV-1 biology that make the development of an HIV vaccine difficult, including viral diversity, effective type of immune response, and suitable experimental model for preclinical trials. In spite of these challenges, recent published results showed that a vaccine regimen could reduce HIV infection rates by 31% in Thailand. This vaccine named as RV144 is composed of a recombinant canarypox vector expressing three HIV-1 proteins as a prime and two different recombinant HIV-1 gp120 envelope glycoproteins with alum adjuvant as a boost. In addition, a subunit vaccine constructed from the viral envelope protein could be efficiently developed using new techniques available through genetic engineering. The current HIV-1 vaccine development focuses on antibody-based approaches. It was shown that immunization with the viral envelope glycoprotein, gp120, should generate neutralizing antibodies that would prevent infection, thereby yielding protective immunity. However, HIV could develop many pathways to escape from antibodies that bind to the different parts of the viral envelope molecules. Thus, the generation of neutralizing antibodies is very difficult after viral infection or immunization protocols. Indeed, the viral envelope molecules (Env) possess glycosylated residues that cover surface epitopes for binding and neutralizing antibodies, even if the antibodies are produced. Furthermore, the trimeric structures of envelope molecules show rapid conformational changes due to the interaction with viral cell surface receptors, CCR5/CXCR4 and CD4; thus the transition state is very poor to be recognized by the immune system. Currently, studies focus on generating stable trimeric envelope molecules (gp120/gp41) as immunogens that can induce neutralizing antibodies that can compete for binding to the cell surface receptors. Altogether, it is clear that the design of a vaccine to elicit HIV-neutralizing antibodies is not straightforward, and it causes major challenges in structural biology and immunology, several other studies strongly suggest cytotoxic T-lymphocyte (CTL)-based immune responses against HIV infections. Indeed, CD8+ T cells play a major role in controlling viral replication during primary HIV infections and in maintaining a stable viral load during the chronic phase. In this line, live-attenuated vaccines could elicit more potent and durable pathogen-specific immune responses than inactivated or subunit vaccines. Generally, DNA vaccines are poorly immunogenic alone, and viral vector vaccines are ineffective due to vector-specific immune responses if used repeatedly; hence, the two approaches have often been tested in combination as prime-boost vaccination strategies. Indeed, the prime-boost vaccination has been considered as an efficient strategy against HIV infections. In this chapter, we will represent challenges to determine the best vaccine strategies against HIV infections.

Part of the book: Advances in Molecular Retrovirology