M.Sc. / Therapeutic and preventative treatment are continually being sought to cease or curtail the worldwide HIV-1 epidemic. At present, therapeutic drug strategies such as highly active anti-retroviral therapy (HAART) have been particularly successful in slowing disease progression and reducing the incidence of AIDS and AIDS related mortality (Detels et al., 1998; Mocroft et al., 1998; Palella et al., 1998). However, the high costs, intricate dosing regimens and limited availability of the HAART drugs (Butera, 2000) has restricted its efficacy in developing and third world countries. As such, available and future drugs will remain inaccessible to the regions that are profoundly affected by the epidemic. An effective vaccine presents a viable solution to the HIV-1 epidemic in these countries. Approximately 70 vaccines are presently in various stages of clinical trials, the majority of which are subtype B specific (Johnston and Flores, 2001). This prevents their use in the predominantly subtype C infected sub-Saharan region of Africa, which accounts for 50% of the global HIV / AIDS population and includes South Africa, statistically the country with the highest number of people living with HIV / AIDS of any country in the world (UNAIDS, 2002). Presently there is no HIV-1 vaccine, regardless of subtype, in clinical use. This owes to several difficulties that hinder the progression of vaccine development, including the lack of predictive animal models, the establishment of viral latency and the difficulty involved in overcoming HIV-1 genetic diversity (Klein, 1999). The expansive HIV-1 genetic variation exhibited by HIV-1 is attributed to a high number of errors made by the reverse transcriptase (RT) enzyme (Coffin, 1992) and the absence of RT proofreading mechanisms during HIV-1 replication (Roberts et al., 1988; Bebenek et al., 1989). The HIV-1 nucleotide sequence drift is most frequently observed in the envelope (env) gene and expressed in env gene products (Shafer et al., 1999). Expression of the variable genome results in the production of progeny strains that are not identical to the parent strain (i.e. HIV-1 exists as a quasispecies within each seropositive individual and between individuals) and contributes to the diverse collection of viral strains in global circulation that vary across and within subtypes. Thus, for an HIV-1 vaccine to be efficient and truly functional it would be required to target this observed hypervariability and be effective against a multitude of currently circulating strains, exhibit cross-clade specificity and remain viable despite the emergence of variant strains. In this study we describe the design, synthesis and immunological ability of a multiple epitope immunogen (MEI) that mimics the hypervariability observed within the third variable (V3) loop of the envelope gp120 region of HIV-1 subtype C. Conjugation to a multiple antigenic peptide (MAP) produces a four -branched (b4) tetrameric peptide construct, designated MEIV3b4. This construct was characterized by theoretical and analytical techniques, tested in a variety of immunological assays and assessed for its potential as a candidate vaccine component. The construct was comparatively analysed through evaluation of three comparison peptides, two of which are hypervariable and based on the V3 region, the other representing a conserved region of HIV-1 envelope. The V3 peptides, named b-MEI-s and poly-L-MEI, differ from the MEIV3b4 construct in that they are less variable and less branched or conjugated to a traditional carrier rather than to a MAP system, respectively. The conserved peptide, designated CCD4 allowed for comparative evaluation between conserved and variable peptides as potential vaccine components. / Dr. Debra Meyer
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uj/uj:7012 |
| Date | 09 May 2008 |
| Creators | Hewer, Raymond |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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