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Annual Review of Medicine 2012HIV-1 and its simian counterpart SIV have been exquisitely tailored by evolution to evade host immunity. By virtue of specific adaptations that thwart individual innate... (Review)
Review
HIV-1 and its simian counterpart SIV have been exquisitely tailored by evolution to evade host immunity. By virtue of specific adaptations that thwart individual innate or adaptive immune mechanisms, and an overall replication strategy that provides for rapid establishment of a large, systemic viral population, capable of dynamic adaptation to almost all immune selection pressures, these viruses, once established, almost invariably stay one step ahead of the host's immune system, and in the vast majority of infected individuals, replicate indefinitely. Although many vaccine approaches tested to date have been able to enhance the magnitude of the immune responses to HIV/SIV infection, most of these responses, whether cellular or humoral, have largely failed to be both effectively antiviral and targeted to prevent the emergence of fully functional escape variants. Recent advances, however, have provided strong evidence that the initial stages of infection following mucosal transmission of these viruses are more vulnerable to immune intervention, and have led to the development of vaccine strategies that elicit responses able to effectively intervene in these early stages of infection, either preventing acquisition of infection or establishing early, stringent, and durable control. Here, we place HIV/AIDS vaccine development in the context of the basic immunobiology of HIV and SIV, review the evidence for their vulnerability to immune responses immediately after mucosal transmission, and discuss how this newly recognized vulnerability might be exploited for the development of an effective HIV/AIDS vaccine.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Allergy and Immunology; Humans
PubMed: 21942424
DOI: 10.1146/annurev-med-042010-085643 -
Current Opinion in HIV and AIDS Nov 2016Models of implementation of known-effective interventions for HIV prevention indicate that an efficacious vaccine to prevent HIV infection would be critical for... (Review)
Review
PURPOSE OF REVIEW
Models of implementation of known-effective interventions for HIV prevention indicate that an efficacious vaccine to prevent HIV infection would be critical for controlling the HIV pandemic. Key issues in the design of future HIV vaccine trials are: first, how to develop reliable immunological correlates of vaccine efficacy, second, how to down-select candidate vaccine regimens into efficacy trials, and third, how to learn about vaccine efficacy in the context of the evolving HIV prevention landscape.
RECENT FINDINGS
Whereas in the past phase-I/-II HIV vaccine trials have addressed the first and second points using a small set of immunological assays and readouts, recently they have used a battery of assays with highly multivariate readouts. In addition, systems vaccinology studies of other pathogens measuring PBMC transcriptomics and other immunological features pre- and postfirst vaccination are demonstrating value, for example, providing discoveries that preimmunization and early postimmunization cell population markers can predict the influenza-specific antibody titer that is a correlate of vaccine protection. The HIV prevention landscape continues to evolve, and the design and analysis of vaccine trials is evolving alongside, to accommodate increasingly dynamic and regional standards of HIV prevention.
SUMMARY
Development of interpretable and robust functional assays, in addition to the associated bioinformatics and statistical analytic tools, is needed to improve the assessment of correlates of protection in efficacy trials and the down-selection of candidate vaccine regimens into efficacy trials. Moreover, high-priority trials should integrate systems vaccinology, including the analysis of prevaccination and early postvaccination markers.
Topics: AIDS Vaccines; Biomarkers; Clinical Trials as Topic; HIV Infections; Humans; Models, Statistical; Treatment Outcome
PubMed: 27662407
DOI: 10.1097/COH.0000000000000314 -
AIDS Research and Human Retroviruses Jun 2011While the long-term goal is to develop highly effective AIDS vaccines, first generation vaccines may be only partially effective. Other HIV prevention modalities such as... (Review)
Review
While the long-term goal is to develop highly effective AIDS vaccines, first generation vaccines may be only partially effective. Other HIV prevention modalities such as preexposure prophylaxis with antiretrovirals (PrEP) may have limited efficacy as well. The combined administration of vaccine and PrEP (VAXPREP), however, may have a synergistic effect leading to an overall benefit that is greater than the sum of the individual effects. We propose two test-of-concept trial designs for an AIDS vaccine plus oral or topical ARV. In one design, evidence that PrEP reduces the risk of HIV acquisition is assumed to justify offering it to all participants. A two-arm study comparing PrEP alone to VAXPREP is proposed in which 30 to 60 incident infections are observed to assess the additional benefit of vaccination on risk of infection and setpoint viral load. The demonstrated superiority of VAXPREP does not imply vaccine alone is efficacious. Similarly, the lack of superiority does not imply vaccine alone is ineffective, as antagonism could exist between vaccine and PrEP. In the other design, PrEP is assumed not to be in general use. A 2 × 2 factorial design is proposed in which high-risk individuals are randomized to one of four arms: placebo vaccine given with placebo PrEP, placebo vaccine given with PrEP, vaccine given with placebo PrEP, or VAXPREP. Between 60 and 210 infections are required to detect a benefit of vaccination with or without PrEP on risk of HIV acquisition or setpoint viral load, with fewer infections needed when synergy is present.
Topics: AIDS Vaccines; Animals; Anti-HIV Agents; Drug Synergism; HIV Infections; Humans; Risk Assessment; Viral Load
PubMed: 21043994
DOI: 10.1089/AID.2010.0206 -
Journal of the International AIDS... Nov 2021The development of a human immunodeficiency virus 1 (HIV-1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly... (Review)
Review
INTRODUCTION
The development of a human immunodeficiency virus 1 (HIV-1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly neutralizing antibodies (bNAbs), which likely involves the use of native-like HIV-1 envelope (Env) trimers at some or all stages of vaccination. Development of such trimers has been very difficult, but much progress has been made in the past decade, starting with the BG505 SOSIP trimer, elucidation of its atomic structure and implementing subsequent design iterations. This progress facilitated understanding the weaknesses of the Env trimer, fuelled structure-guided HIV-1 vaccine design and assisted in the development of new vaccine designs. This review summarizes the relevant literature focusing on studies using structural biology to reveal and define HIV-1 Env sites of vulnerability; to improve Env trimers, by creating more stable versions; understanding antibody responses in preclinical vaccination studies at the atomic level; understanding the glycan shield; and to improve "on-target" antibody responses versus "off-target" responses.
METHODS
The authors conducted a narrative review of recently published articles that made a major contribution to HIV-1 structural biology and vaccine design efforts between the years 2000 and 2021.
DISCUSSION
The field of structural biology is evolving at an unprecedented pace, where cryo-electron microscopy (cryo-EM) and X-ray crystallography provide complementary information. Resolving protein structures is necessary for defining which Env surfaces are accessible for the immune system and can be targeted by neutralizing antibodies. Recently developed techniques, such as electron microscopy-based polyclonal epitope mapping (EMPEM) are revolutionizing the way we are analysing immune responses and shed light on the immunodominant targets on new vaccine immunogens. Such information accelerates iterative vaccine design; for example, by reducing undesirable off-target responses, while improving immunogens to drive the more desirable on-target responses.
CONCLUSIONS
Resolving high-resolution structures of the HIV-1 Env trimer was instrumental in understanding and improving recombinant HIV-1 Env trimers that mimic the structure of viral HIV-1 Env spikes. Newly emerging techniques in structural biology are aiding vaccine design efforts and improving immunogens. The role of structural biology in HIV-1 vaccine design has indeed become very prominent and is unlikely to diminish any time soon.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Cryoelectron Microscopy; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 34806305
DOI: 10.1002/jia2.25797 -
Retrovirology Jul 2013The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1... (Review)
Review
The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1 acquisition in the RV144 phase III trial, and because a series of potent and broad spectrum neutralizing antibodies have been isolated from infected individuals. Taken together, these two findings suggest ways forward to develop a neutralizing antibody-based vaccine. However, understanding of the correlates of protection from disease in HIV-1 and other infections strongly suggests that we should not ignore CTL-based research. Here we review recent progress in the field and highlight the challenges implicit in HIV-1 vaccine design and some potential solutions.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Antibodies, Neutralizing; Clinical Trials as Topic; Drug Discovery; HIV Antibodies; HIV-1; Humans; T-Lymphocytes, Cytotoxic
PubMed: 23866844
DOI: 10.1186/1742-4690-10-72 -
Current Opinion in HIV and AIDS Nov 2016A vaccine that elicits antibody responses that can neutralize the diversity of HIV clades has not yet been achieved, and is a major focus of HIV vaccine research. Here,... (Review)
Review
PURPOSE OF REVIEW
A vaccine that elicits antibody responses that can neutralize the diversity of HIV clades has not yet been achieved, and is a major focus of HIV vaccine research. Here, we provide an update on the barriers to eliciting such antibodies, and how advances in immunogen design may circumvent these roadblocks, focusing on data published in the last year.
RECENT FINDINGS
Studies of how broadly neutralizing antibodies (bNAbs) develop in HIV-infected donors continue to produce key insights, suggesting that for some viral targets there are common pathways to developing breadth. Germline-targeting strategies, that aim to recruit rare precursors of bNAbs, have shown promise in immunogenicity studies, and structural biology has led to advances in immunogen design. Mapping of strain-specific tier 2 vaccine responses has highlighted the challenges that remain in driving antibodies toward breadth.
SUMMARY
Elucidation of the HIV envelope structure, together with an understanding of how bNAbs emerge in vivo has guided the design of new immunogens and vaccine strategies that show promise for eliciting protective antibodies.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Antigens, Viral; HIV; HIV Antibodies; Humans
PubMed: 27559709
DOI: 10.1097/COH.0000000000000317 -
Nanomedicine (London, England) Mar 2017The development of a successful vaccine against HIV is a major global challenge. Antiretroviral therapy is the standard treatment against HIV-1 infection. However, only... (Review)
Review
The development of a successful vaccine against HIV is a major global challenge. Antiretroviral therapy is the standard treatment against HIV-1 infection. However, only 46% of the eligible people received the therapy in 2015. Furthermore, suboptimal adherence poses additional obstacles. Therefore, there is an urgent need for an HIV-1 vaccine. The most promising clinical trial to date is Phase III RV144, which for the first time demonstrated the feasibility of vaccine-mediated immune protection against HIV-1. Nevertheless, its 31% efficacy and limited durability underscore major hurdles. Here, we discuss recent progress in HIV-1 vaccine development with a special emphasis on nanovaccines, which are at the forefront of efforts to develop a successful HIV-1 vaccine.
Topics: AIDS Vaccines; HIV Infections; HIV-1; Humans; Nanoparticles
PubMed: 28244816
DOI: 10.2217/nnm-2016-0381 -
Current Opinion in HIV and AIDS Mar 2019CMV-vectored vaccines expressing SIV antigens have mediated unprecedented levels of virus control following SIV challenge in rhesus macaques. Remarkably, protection was... (Review)
Review
PURPOSE OF REVIEW
CMV-vectored vaccines expressing SIV antigens have mediated unprecedented levels of virus control following SIV challenge in rhesus macaques. Remarkably, protection was dependent on nonclassically restricted CD8 T cells. Here, we review the latest research in CMV-vectored vaccines in both humans and nonhuman primates as well as recent advances in the understanding nonclassically restricted T cells, particularly MHC-E-restricted CD8 T cells.
RECENT FINDINGS
Recent studies have investigated human translation of CMV-vectored vaccines including studies to ensure vaccine vector safety. Other work has focused on testing of animal models to investigate the relative contribution of MHC diversity and CMV strain on T-cell induction. Lastly, several groups have investigated MHC-E peptide binding, including HLA-E, have found that MHC-E can accommodate different peptide motifs, consistent with the original observations in CMV-vaccinated macaques.
SUMMARY
CMV remains a promising vaccine vector with the potential to be protective against multiple diseases, including HIV. However, CMV is highly species-specific and in humans, congenital infection can lead to serious birth defects. To ensure safe translation to humans, further clinical and animal studies are needed to better understand CMV-vectored immunity as well as more basic immunological questions relating to the induction of classical vs. nonclassical T cells.
Topics: AIDS Vaccines; Animals; Cytomegalovirus; Genetic Vectors; HIV; HIV Infections; Humans
PubMed: 30562176
DOI: 10.1097/COH.0000000000000524 -
Viruses Dec 2013Equine infectious anemia (EIA), identified in 1843 [1] as an infectious disease of horses and as a viral infection in 1904, remains a concern in veterinary medicine... (Review)
Review
Equine infectious anemia (EIA), identified in 1843 [1] as an infectious disease of horses and as a viral infection in 1904, remains a concern in veterinary medicine today. Equine infectious anemia virus (EIAV) has served as an animal model of HIV-1/AIDS research since the original identification of HIV. Similar to other lentiviruses, EIAV has a high propensity for genomic sequence and antigenic variation, principally in its envelope (Env) proteins. However, EIAV possesses a unique and dynamic disease presentation that has facilitated comprehensive analyses of the interactions between the evolving virus population, progressive host immune responses, and the definition of viral and host correlates of immune control and vaccine efficacy. Summarized here are key findings in EIAV that have provided important lessons toward understanding long term immune control of lentivirus infections and the parameters for development of an enduring broadly protective AIDS vaccine.
Topics: AIDS Vaccines; Animals; Antigenic Variation; Drug Discovery; Equine Infectious Anemia; Genetic Variation; Horses; Humans; Infectious Anemia Virus, Equine
PubMed: 24316675
DOI: 10.3390/v5122963 -
Nature Immunology Nov 2018In this Review, we highlight some recent developments in the discovery and application of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV);... (Review)
Review
In this Review, we highlight some recent developments in the discovery and application of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV); i.e., antibodies able to neutralize diverse isolates of HIV. We consider the characterization of novel bnAbs, recent data on the effects of bnAbs in vivo in humans and animal models, and the importance of both kinds of data for the application of Abs to prophylaxis and therapy and to guide vaccine design. We seek to place newly discovered bnAbs in the context of existing bnAbs, and we explore the various characteristics of the antibodies that are most desirable for different applications.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; Humans
PubMed: 30333615
DOI: 10.1038/s41590-018-0235-7