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• W2012012357 abstract "With nearly 14 000 people becoming newly infected with HIV-1 every day, a vaccine must be a global health and development priority of the highest order. Vaccines generating neutralizing antibodies at mucosal sites are of particular interest because most HIV-1 infections worldwide are acquired by sexual transmission. To highlight these questions a symposium entitled ‘HIV neutralizing antibodies: relevance to pathogenesis and vaccines’ was held at the Nobel Forum, Karolinska Institutet, Stockholm, Sweden, in October 2006. This issue of JIM contains three reviews of topics that were discussed at the symposium. Even if the relevance of neutralizing antibodies in HIV-1 protection and pathogenesis remains to be defined, animal models show that antibodies have the unique ability to prevent the acquisition of AIDS virus infection. Therefore, production of an antibody response with broad neutralizing activity against primary isolates of multiple HIV-1 subtypes continues to be a desired characteristic of candidate HIV-1 vaccines. Standardization of read-out systems for such an induced immune response also remains a high priority in current vaccine programmes. Control of established HIV-1 infection has mainly been attributed to the cellular arm of the immune response. However, the humoral arm is coming into focus again as antibodies – induced by the infection or administered passively – may control virus replication to some extent. One mechanism of antibody-mediated neutralization is interference with HIV-1 entry into target cells. Target epitopes include (i) the CD4 receptor binding site in HIV-1 gp120, (ii) carbohydrate structures in HIV-1 gp120, (iii) CD4-induced co-receptor binding sites in HIV-1 gp120; and (iv) HIV-1 gp41 structures that are exposed during the very last step of entry, membrane fusion. Neutralizing antibodies may also bind to cellular receptor sites implicated in HIV-1 entry such as the chemokine receptor CCR5. Antibodies can also exert their virus inhibiting effect by simply cross-linking virus particles, leading to high molecular aggregates that can be eliminated by phagocytosis. Killing of infected cells, in addition to neutralizing cell-free viral particles, can be mediated by antibodies mediating cellular cytotoxicity (ADCC) as well as by activating the complement cascade. On the other hand, antibodies may indeed have infection-enhancing effects, especially after immunization with whole virus particles. Antibody production is dependent on an intact B-cell repertoire. However, during both primary and chronic stages of HIV infection, a reduction in specific antibody titres has been found, and was shown to be a direct consequence of loss of memory B cells [1]. The significance of this finding must be taken into account when trying to stimulate the humoral arm of the immune response with vaccine candidates. In one of the reviews from the above conference, Drs Huber and Trkola [2] focused on the role of antibody-mediated effector functions (ADCC, phagocytosis and complement activation) in relation to HIV infection and vaccines. The past 20 years have generated key information on epitope specificity, potency, breadth and in vivo activity of the neutralizing antibodies, but still there is uncertainty about whether Fc-mediated mechanisms are largely beneficial or detrimental for the host. The authors give their view on the current knowledge on the manifold functions of the humoral immune response in HIV infection, their underlying mechanisms and potential in vaccine-induced immunity. On HIV-1, the envelope spike is the only viral target available for neutralizing antibodies. The envelope spike is composed of three copies of the HIV-1 gp120 exterior envelope glycoprotein and three gp41 transmembrane glycoprotein molecules. These envelope structures are involved in binding and fusion of the virus to their target cells. However, there is a remarkable diversity, glycosylation and conformational flexibility of the HIV-1 envelope that allow it to evade antibody-mediated neutralization. Broad neutralization to several different HIV-1 subtypes is therefore likely to result from multiple specificities of antibodies and indeed, monoclonal antibodies that elicit broad neutralizing activity target both HIV-1 gp120 and HIV-1 gp41 epitopes. Thus, the step-wise infection process involving subsequent binding of two different receptors is an efficient mechanism to protect viral epitopes functionally important for infection from neutralizing antibodies. The molecular structure of the SIV envelope spike was recently visualized [3].The resulting model yields information also of relevance for HIV-1 relating to the exposure of the receptor binding surfaces and reveals surfaces relevant to antibody neutralization. Unfortunately the functional HIV-1 envelope structure is labile such that immunogens based on it contain monomeric or irrelevant forms of HIV-1 gp120 and HIV-1 gp41 that mainly elicit nonneutralizing antibodies. But, despite the complex picture, the HIV-1 envelope retains conserved determinants that mediate binding to the CD4 molecule. Such a vulnerable site, related to a functional requirement for efficient association with CD4, was recently structurally defined and is the target structure for a broadly neutralizing monoclonal antibody ‘b12’ [4]. Even though this antibody has been used successfully in passive immunization experiments, it may not provide protection against all HIV-1 variants representative of those that are spreading in endemic areas. Pseudoviruses with subtype A HIV-1 envelopes from early infection demonstrated a broad range of neutralization sensitivities including poor neutralization by ‘b12’ [5]. Thus, one may speculate that even though neutralizing antibodies target conserved viral structures and bind efficiently it may not be sufficient to protect against subsequent infection. Sexually transmitted viruses of the appropriate phenotype (‘R5’) isolated from early infection and of different subtypes that are common globally must be included in any evaluation of challenge viruses, potential vaccines and other virus-specific intervention strategies [6]. Phogat et al. [7] address the difficulties of inducing HIV-1 neutralization in relation to vaccines in the current issue. Vaccine-induced antibodies that block viral entry provide the protective mechanism of most existing prophylactic vaccines. However, for highly variable viruses such as HIV-1, the ability to elicit broadly neutralizing antibody responses through prophylactic vaccination has proved to be extremely difficult. The major challenge in the development of an HIV-1 vaccine that elicits broadly neutralizing antibodies thus lies in the design of suitable HIV-1 envelope glycoprotein immunogens. The review describes viral and cellular molecules that potentially could act as targets for antibodies, or antibody-related molecules, to block HIV-1 entry into susceptible target cells and decrease the spread of HIV-1 in the human population. The development of HIV-1 vaccines and microbicides (products applied locally at the time of sexual intercourse) remains hindered by our limited understanding of correlates of immune protection to infection. One approach to identify HIV-1 vaccine or microbicide candidates is to dissect the natural immune response against the virus in individuals controlling the infection over decades (long-term nonprogressors, LTNP) or those who seem to resist infection despite multiple exposure to the virus (exposed uninfected individuals, EUI). Another approach is to dissect why broadly cross-neutralizing activity is present in the sera of HIV-2-infected but not HIV-1-infected individuals [8]. In both EUI and LTNP individuals, natural antibodies directed to cellular proteins involved in the HIV-1 entry process have been identified [9]. In particular, HIV-1 infection blocking anti-CCR5 IgA and IgG antibodies have been found. A possible mechanism for their protective role is through long-lasting down-regulation of the corresponding receptor. These antibodies do not seem to affect immune function due to the redundancy of expression of receptors included in the chemokine family. Evidence indicating that resistance to HIV-1 infection at mucosal sites is possible comes from cohorts of female commercial sex workers and HIV-1 discordant couples. Despite repeated sexual exposure to the virus for years, some of these individuals remain uninfected. Surprisingly, HIV-1 exposure stimulates a mucosal and systemic HIV-1 specific humoral and cellular immune response. In this issue, Hirbod and Broliden [10] describe the presence of HIV-1-specific IgA antibody responses and secreted immune molecules of the innate immune system in the female genital tract from these individuals. Knowledge of these immune responses needs to be combined with future studies on the expression of HIV-1 target cells and viral receptors in the genital tract of both men and women. This has been recently highlighted by studies showing that male circumcision is associated with a risk reduction in HIV-1 acquisition of more than 50% [11]. Today few, if any, researchers believe that it will be possible to develop an HIV-1 vaccine unless we can overcome the ability of the virus to evade humoral immunity at both the mucosal and systemic sites. Without doubt HIV-1 neutralization and humoral immunity will continue to be an area of intense research in the years to come. Hopefully these efforts will enable true advances in the search for an effective HIV-1 vaccine. No conflict of interest was declared." @default.
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• W2012012357 title "Introduction: HIV neutralizing antibodies: relevance to pathogenesis and vaccines" @default.
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