Viral sequence diversity: challenges for AIDS vaccine designs

Abstract

Among the greatest challenges facing AIDS vaccine development is the intrinsic diversity among circulating populations of HIV-1 in various geographical locations and the need to develop vaccines that can elicit enduring protective immunity to variant HIV-1 strains. While variation is observed in all of the viral proteins, the greatest diversity is localized to the viral envelope glycoproteins, evidently reflecting the predominant role of these proteins in eliciting host immune recognition and responses that result in progressive evolution of the envelope proteins during persistent infection. Interestingly, while envelope glycoprotein variation is widely assumed to be a major obstacle to AIDS vaccine development, there is very little experimental data in animal or human lentivirus systems addressing this critical issue. In this review, the state of vaccine development to address envelope diversity will be presented, focusing on the use of centralized and polyvalent sequence design as mechanisms to elicit broadly reactive immune responses.

Figure 1. Genomic organization of the HIV-1 proviral genome

Structural and enzymatic proteins are encoded by the gag, pol and env genes. Regulatory gene products are encoded by the tat and rev genes and the major regulatory proteins are encoded by the vif, vpu, vpr and nef. The long terminal repeats (LTRs) are sites for initiation of viral RNA synthesis and necessary for proviral integration into host cell chromosomes.

Figure 2. Schematic of HIV-1 envelope

(A) shows the division of Env_gp160 into Env_gp120 and Env_gp41, as well as the regions of envelope and their location within Env_gp120 and Env_gp41. (B) A schematic of folded Env_gp120. The constant regions are shown in blue with the variable regions shown in purple. Disulfide bonds are shown in green. ICD: Intracytoplasmic domain.

Figure 3. HIV-1 is divided into three groups: (M) main, (O) outlier and (N) non-M/non-O

Groups M, O and N are shown as large ovals. Group M is further divided into clades, which are shown as small ovals arrows pointing from the group M oval. Clades A and F have also been further divided into A1/A2 and F1/F2.

Figure 4. Centralized vaccines

Three methods of developing a centralized vaccine. (A) Ancestral vaccine. This method of centralization utilizes the theoretical ancestor that gave rise to the phylogenetic tree. The location of the ancestral vaccine is shown with a green dot. (B) Center of the tree. This method of centralization generates a sequence that is equidistant to all points of the phylogenetic tree. The approximate location of the vaccine sequence is shown with a green dot. (C) Consensus vaccine. A consensus sequence was generated from the seven sample envelope sequences by assigning the most common amino acid at each position in the amino acid sequence.

Figure 5. Polyvalent vaccines

Three main methods of developing a polyvalent vaccine. (A) Single-component vaccine. These polyvalent vaccines are composed of a single repeated component shown as an oval. These vaccines can be based on a single clade shown in blue or multiple clades as demonstrated by multiple colors. (B) Multiple-component vaccine. These polyvalent vaccines are composed of two or more target proteins and can also be based on single or multiple clades. One antigen is shown as a square with the second antigen being shown as an oval. (C) Polyvalent peptide vaccines. These vaccines are designed to present the most common cellular epitopes from a population of sequences to the immune system. The different colors represent different epitopes.