Enhancing immunogenicity and cross-reactivity of HIV-1 antigens by in vivo targeting to dendritic cells

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    ISSN 1743-588910.2217/NNM.12.131 2012 Future Medicine Ltd Nanomedicine (2012) 7(10), 15911610

    Enhancing immunogenicity and cross-reactivity of HIV-1 antigens by in vivo targeting to dendritic cells

    BackgroundHighly active antiretroviral treatment (HAART) inhibits the replication of HIV and slows down disease progression, thus keeping viral RNA levels very low [1]. However, alternative treat-ment strategies are required as there are still a number of unresolved problems with HAART. These include high cost, persistent low-grade viral replication, incomplete normalization of T-cell functions, drug-related side effects (lipid metabolism problems: lipodystrophy and athero-sclerosis) and emerging primary HIV infections with multidrug-resistant viruses [2].

    During the past two decades, a plethora of immunotherapeutic strategies and HIV vaccines have been developed to treat AIDS. Although these induce a certain level of immune response, they are not associated with significant clinical benefit or with an effective and sustained control of viral replication [35]. Nevertheless, a study by Lvy et al. demonstrated that immunization in combination with antiretroviral therapy and IL-2 improves HIV-specific immunity and lowers the viral set-point after withdrawal of HAART [6]. Lu et al. showed that ex vivo pulsed autologous monocyte-derived dendritic cells (DCs) with inactivated autologous virus induce a prolonged reduction of HIV RNA in a substantial num-ber of patients [7]. These results highlighted the potential of immunotherapy strategies targeting HIV antigens to DCs in HIV-infected patients.

    The mutation capacity of HIV implies that an infected patient may harbor many genetic variants of the virus. This is undoubtedly a major obstacle for the development of a vaccine

    for all variants. However, more than 90% of infections belong to HIV-1 group M [8], which includes at least nine genetically distinct sub-types (or clades). Of these, clade C (HIV-C) strains comprise 56% of all HIV infections worldwide. Therefore, HIV vaccines must include protection against this virus subtype.

    While live-inactivated HIV vaccines are strongly immunogenic and can induce both cellular and humoral immune responses, their use remains a major concern because of the risk of HIV mutating back or recombining with a pathogenic virus. Although virus-inactivated vaccines are still being used because of the sim-plicity in obtaining an autologous virus, new HIV vaccine research has focused mainly on the administration of conserved recombinant viral proteins and peptides as single preparations or cocktails. Attention has also been devoted to DNA encoding several HIV antigens, recom-binant vectors and primeboost strategies, using two vaccination approaches to immunize with the same antigen (Figure 1 shows the genome and virion organization with the potential antigens).

    The expression of HIV genes in DCs could induce a response mediated through MHC class I molecules to generate cytotoxic T-lymphocytes (CTLs). In addition, HIV Tat protein stimu-lates the maturation of DCs and increases their antigen-presenting capacity, thereby promot-ing the induction of antigen-specific T-cell responses [9,10]. Recently, several DC-based HIV vaccines have produced encouraging results, thereby indicating that some HIV anti-gens those more invariant or essential for viral

    Current retroviral treatments have reduced AIDS to a chronic disease for most patients. However, given drug-related side effects, the emergence of drug-resistant strains and the persistence of viral replication, the development of alternative treatments is a pressing need. This review focuses on recent developments in HIV immunotherapy treatments, with particular emphasis on current vaccination strategies for optimizing the induction of an effective immune response by the recruitment of dendritic cells. In addition to cell-based therapies, targeted strategies aiming to deliver synthetic HIV peptides to dendritic cell-specific receptors in vivo will be discussed.

    Keywords: carrier conjugates n cross-reactivity n delivery vehicle n HIV-1 n immunogenicity n nanoparticle n specific ligands n synthetic peptide vaccines n targeting n V3 loop

    Luis J Cruz1,2*, Felix Rueda3, Paul Tacken1, Fernando Albericio2,4, Ruurd Torensma1 & Carl G Figdor11Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands 2Institute for Research in Biomedicine and CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain 3Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain 4School of Chemistry, University of KwaZulu-Natal, 4041 Durban, South Africa *Author for correspondence: Endocrinology Research Lab and Molecular Imaging, Leiden University Medical Center, Building 1, C4-R67, Albinusdreef 2, 2333ZA Leiden, The Netherlands l.j.cruz_ricondo@lumc.nl

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    Review Cruz, Rueda, Tacken, Albericio, Torensma & Figdor

    U3 R U5




    PR RT IN



    vpr rev env


    SU TM


    Surface (GP120) SU

    Transmembrane(GP41) TM

    Nucleocapsid (p24) NCMatrix MA

    Integrase IN (p32)

    Reverse transcriptase(p66)

    p6, vif, vpr, nef

    Protease PR(p11)

    Transmembrane(GP41) TMSurface (GP120) SU

    100 200 300 400 500 600 700

    V1 V2 V3 V4 V5

    Variable domains (gp120)


    Fusion domainProteolyticcleavageCD4-binding domainV3 loop


    Nanomedicine Future Science Group (2012)

    Figure 1. HIV-1 genome and virion organization: the potential use of virus proteins for vaccines. The genome of HIV has the characteristics of a lentivirus. It is composed of two LTR regions, which are involved in the replication and integration of the virus. Three regions, gag, pol and env, code for NC and MA, enzymatic proteins (protease, reverse transcriptase and integrase) and envelope proteins, respectively, and a set of accessory proteins (tat, nef, vpr, vif). Gag (p55) polyprotein is processed during maturation to MA (p17), capsid protein (p24), spacer peptide 1 (p2); NC (p7), spacer peptide 2 (p1) and p6. Pol codes for viral enzymes reverse transcriptase, integrase and HIV protease. The most frequently used proteins in HIV vaccine development are Env, envelope glycoproteins and glycoprotein (gp)120 (SU or gp120) in particular. The latter contains variable regions, such as the V3 loop. Consisting of approximately 30 amino acids, this loop is formed by two cysteine residues that form a disulfide bridge, and it has a conserved GPGRAF amino acid sequence at the perimeter. The remainder of the loop is more variable. Gp120 is known to bind with high affinity to the cellular protein CD4. After binding, this glycoprotein binds to cellular chemokine receptors, notably CCR5. The other is a transmembrane glycoprotein (TM or gp41), which contains highly hydrophobic residues in a short segment of the N-terminal (fusion) domain. This region of fusion is crucial because it allows the membrane of the virion to fuse with the cell membrane and thus allows virus entry into the cell. In addition to the fusion region, gp41 has a second hydrophobic region in the middle, which serves to anchor the protein to the lipid bilayer of the viral envelope. The gp120 and gp41 proteins are produced by fragmentation of a large precursor, gp160, and are found as oligomers on the viral particle. LTR: Long terminal repeat; MA: Matrix proteins; NC: Nucleocapsid; TM: Transmembrane glycoprotein.

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    Enhancing immunogenicity & cross-reactivity of HIV-1 antigens by in vivo targeting to DCs Review

    replication generate specific T lymphocytes in subjects with long-term stable disease [1113].

    direct antigen vaccination using a series of presentation strategies for HIV-1Given that many of the vaccine candidates cur-rently available induce antigen-specific antibody responses and do not cross-react with heterolo-gous strains, improvements in HIV-1 vaccines are needed. To overcome the problem of HIV-1 variability, novel vaccines should be designed to induce an extensive range of reactive antibodies against multiple HIV-1 epitopes. In this regard, the authors and others have focused on achieving a good immunogen on the V3 loop of the HIV-1 envelope. This loop was chosen because it is the most variable region and is responsible for induc-tion. It is also the primary target of many neu-tralizing antibodies [14], and it is involved in vari-ous other aspects that affect infectivity. Thus, sequence changes in V3 affect chemokine recep-tor usage and therefore modulate the cell types infected [15]. Moreover, it appears that antibodies against the principal neutralizing domain of V3 exert control over viral load [16]. For the HIV-1 MN subtype B isolate, a high titer against V3 has been correlated with slow progression rates in seropositive hemophilic Japanese patients [17]. All these findings highlight the immunological relevance of the V3 loop which, in addition, includes both T-helper and CTL epitopes [18], thereby justifying its inclusion in a number of HIV-1 vaccine candidates [19]. However, in a recent report from the RV144 trial, in a vaccine composed of a recombinant canarypox vector expressing HIV-1, gag, pro and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E) (one of the few vaccines that has shown some protection against HIV-1), the T-cell responses were preferentially targeted to epi