- Open Access
Clade, Country and Region-specific HIV-1 Vaccines: Are they necessary?
© Slobod et al; licensee BioMed Central Ltd. 2005
- Received: 01 April 2005
- Accepted: 28 April 2005
- Published: 28 April 2005
Today, scientists are often encouraged to custom-design vaccines based on a particular country or clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor to produce a unique vaccine for every world region or virus subtype may not be necessary.
- World Region
- Infected Subject
- Encode Protein Sequence
- Bind Target Cell
- Cocktail Vaccine
It is generally agreed that HIV-1 arose decades ago by transfer of virus from chimps to humans . The subsequent travel of infected persons and the continued practice of high-risk behaviors fostered virus transmission to virtually every world region. Once HIV-1 awareness was heightened and HIV-1 sequencing projects were implemented, regional similarities of viral sequences, presumably a consequence of the founder effect, became evident. Clade designations (e.g. clade A, B, C) were then used as a means to categorize viruses based on genetic sequence; thus such clade designations also tended to cluster viruses according to geographical location. Today, due to continuous virus transmission, mutation and recombination, the demarcation of HIV-1 subtypes has become increasingly blurred, and the categorization of viruses by clade is increasingly difficult [2–5]. Nonetheless scientists are currently encouraged to custom-design vaccines based on a particular country or clade [6–11]. To this end, a single viral sequence may be selected, possibly based on a formula of ancestry or consensus, to represent all other viruses in the targeted category.
Designing vaccines in this way prompts careful consideration: must a unique vaccine be prepared to represent every clade, country or region of the world? If so, how will this be accomplished and for which country should first vaccines be produced? Who will decide? The complexity of such an undertaking and the many difficulties that attend it encourage a second look at the strategy. Review of the scientific literature may provide reassurance that the seemingly unachievable endeavor to custom-produce a vaccine for every clade, country or region may not be necessary.
While differences in encoded protein sequence may permit discrimination between certain HIV-1 subtypes, successful vaccine development requires that viral proteins elicit protective immune responses, regardless of sequence. It has long been known that clades, as defined by genetic sequence, do not correspond to immunotypes, as defined by mutually exclusive immune responses [12–14]. Both B- and T-cells elicited by a virus from one clade may recognize viruses from other clades. This cross-clade responsiveness is explained by the fact that the B- and T-cells recognize precise epitopes rather than the overall sequence similarity of viruses. Antibody binding depends on three-dimensional structure, and the molecular structures bound by antibodies can occur on proteins that differ widely in primary sequence. T-cells recognize peptides in association with Class I or Class II MHC molecules, but like B-cells, T-cells can cross-react with non-identical targets. Conversely, two viruses may have 99% sequence similarity, yet a particular neutralizing antibody or T-cell receptor may discriminate between them. This discrimination may be due to a single amino acid change within the receptor contact site or in a sequence that alters epitope display [15, 16]. Thus it is the detail of epitope and epitope context, not overall sequence similarity that defines lymphocyte specificity.
Perhaps careful vaccine formulation will preclude the need for assembly of enormous cocktails. Consideration that envelope structure is constrained by function suggests that the formulation of an effective envelope-based vaccine is feasible. The virus envelope must bind target cells to mediate infection, and only a few target cell receptor molecules (e.g. CD4, CCR5, CXCR4), have been described. Therefore, the number of discrete envelope shapes that maintain full cell-binding potential and function is likely to be limited . Because the virus envelope is the target of both neutralizing antibodies and T cells, the strengths of both arms of the immune system may be harnessed by an envelope-based vaccine cocktail [28–30]. Diverse proteins need not be cross-inhibitory. In fact, type-specific immune responses have been recognized toward a single envelope construct represented as only 1% of a mixed vaccine . Cocktail vaccines are effective in controlling other diverse pathogens (e.g. pneumococcus, poliovirus), despite early doubts about their prospect of success .
The assembly of envelope cocktail vaccines will probably be necessary to represent the natural diversity of HIV-1, even within a single clade. Careful vaccine design may reveal a cocktail formulation able to prevent virus infections in every world region, and to overcome the political and financial dilemmas associated with the production of clade, country or region-specific vaccines.
This work was supported in part by NIH NIAID P01-AI45142, NCI Cancer Center Support Core Grant P30-CA21765, the Mitchell Fund, the Federated Department Stores, the James B. Pendleton Charitable Trust and the American Lebanese Syrian associated Charities (ALSAC).
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