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• W2072675622 abstract "With the discovery of HIV as the cause of AIDS in 1983 [1] came the hope that a vaccine could be developed just as it was for other viral diseases epitomized by smallpox and polio, both the subject of successful vigorous global vaccination efforts aimed at their eradication [2,3]. Recent scientific findings have brought new perspectives into the understanding of the human immune response to HIV infection, which can and should be used toward the goal of developing a preventive vaccine, including the re-evaluation of the use of inactivation of HIV as a viable strategy to this end [4]. During the early years of the HIV pandemic, it became known that HIV could be detected by the use of highly sensitive nucleic acid testing technologies that could detect wild-type HIV infections in seronegative individuals [5]. These plasma wild-type HIV isolates could only be propagated in co-cultures with primary lymphoid cell substrate [6] and lacked genetic mutations that result from pressure by the host immune response [7]. There is conceptual recognition that the characterization of these early founder viruses is important in understanding the process of transmission of HIV. Such an understanding should be of significance in the development of an HIV vaccine. However, until recently, approaches used for such characterization have been hampered by technical difficulties, which have not allowed the unambiguous identification of the transmitted or early founder virus or viruses responsible for the establishment of a productive HIV infection. A detailed description of such methodological difficulties is beyond the scope of this article and are described elsewhere [8–10]. These technical difficulties such as Taq-induced nucleotide misincorporation and of recombination in finished sequences have been resolved by the use of single genome amplification (SGA) of HIV plasma viral ribonucleic acid. This is followed by direct sequencing of uncloned amplicon DNA [11,12]. SGA-based analysis applied to recently HIV-infected patients enables the unambiguous identification of the transmitted or early founder env genes of viruses responsible for the establishment of a productive HIV infection. Different groups have fully sequenced different numbers of transmitted/founder viruses using this approach and their characterization and common phenotypic properties have been extensively described particularly for both, B and C subtypes [13,14]. The characterization and properties of transmitted/founder viruses have been published and accepted by the scientific community with regard to HIV transmission pathogenesis and its potential to vaccine development. In general, the common phenotypic traits that are accepted as defining transmitted/founder viruses are higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative interferon (IFN) α resistance [14]. Transmitted/founder viruses are currently available as reagents from National Institutes of Health(Bethesda, Maryland, USA) in the form of plasmids that can be reconstructed as infectious molecular clones for use in research related to the biology of HIV transmission and vaccine development. One key observation of these studies has been the relative ease with which transmitted/founder viruses are neutralized by the initial autologous neutralizing antibodies of germline or unmutated common ancestors antibodies (UCAs) [4,13], indicating that transmitted/founder viruses contain epitopes that when presented to the immune system generate neutralizing antibodies. It seems evident that if the transmitted/founder virus does not infect the host, there would be no need for highly mutated broad neutralizing antibodies to prevent infection because they are the result of evolutionary pressures resulting from chronic infection [15], which would not occur if the initial transmitted/founder virus is prevented from infecting the host's permissive cells. Can this immune response to transmitted/founder viruses be harnessed as a tool to prevent the transmission of HIV? As four clades (A through D) and two circulating recombinant forms (01 and 02), both of which are 70% clade A, account for 90% of all infections worldwide [16], we suggest an approach similar to that used in the generation of the inactivated Salk poliovirus vaccine. In the case of the inactivated polio vaccine, the inactivation of three wild, virulent reference strains led to the development of a polyvalent preventive polio vaccine [17]. At the Baylor College of Medicine, Center for AIDS Research laboratory, we have recently demonstrated the use of a targeted inactivation of HIV reverse transcriptase using a nonmicrobicidal ultraviolet wave length irradiation of a photo-labeled nonnucleoside reverse transcriptase inhibitor. This research resulted in numerous, complete successive inactivations of different suspensions of HIV viral particles [18]. Although there are differences in the envelopes of transmitted/founder viruses when compared with chronic viruses, a method of inactivation, such as ours, is based on the targeted inactivation of reverse transcriptase and thus there should be no expectation of a change or difference in sensitivity to the inactivation methodology between transmitted/founder viruses and other chronic viruses [19]. With the availability of clones of transmitted/founder viruses and a new method of HIV inactivation, we believe such a process is capable of eliminating the infectiousness of HIV with potential to preserve its full antigenic structure. The result could be the creation of an inactivated whole-virus polyvalent vaccine with the most frequent subtypes of transmitted/founder viruses. This concept of targeting the transmitted/founder virus for development of an effective HIV vaccine receives support from other investigators proposing the use of inactivated transmitted/founder viruses as a pooled biological product representing different HIV clades [6,20]. Inactivation is a proven approach to viral and bacterial vaccine development [21]. The past failures of an inactivated or ‘killed’ virus approach to the development of a preventive HIV vaccine have multifactorial causes including the harshness of inactivation methods used (formalin, aldithriol-2, or heat combined with formalin or aldithriol-2) all characterized by severe denaturing of important HIV epitopes and proteins [21]. In addition, biological characteristics of the first HIV strains used to prepare the initial inactivated vaccines may have influenced their effectiveness. An example of such characteristics is the known phenomenon of ‘gp 120 shedding’ from prototype T-cell adapted viruses [22]. All these factors may have contributed to the inefficient generation of a significant immune response to these prototypes of inactivated HIV vaccines and in part may explain the failure of previous attempts to develop an inactivated or killed HIV vaccine. Nonetheless, these methods tested in vitro and in animal models have revealed some measure of generation of neutralizing antibodies. Inactivation of HIV with beta-propiolactone, binary ethylenimine, and formaldehyde led to the development of an inactivated (‘killed’) vaccine capable of inducing antibodies that recognize homologous and heterologous strains of HIV-1 [23]. Sublethal doses of formalin followed by heat inactivation at 62°C have been shown to induce in mice and nonhuman primates modest but significant titers of antibodies capable of neutralizing heterologous primary isolates of HIV in a variety of infectivity assays [24]. HIV or simian immunodeficiency virus have been inactivated by the use of 2,2′-dithiopyridine (aldithriol-2) resulting in preparations of inactivated viral particles which when studied in the simian immunodeficiency virus/macaque model did not protect vaccinated monkeys against infection with wild-type virus but decreased viremia after challenge with no significant depletion of CD4+ cells [25]. These results although not completely successful, suggest that the refinement of an inactivation methodology could provide a platform for effectiveness, considering the availability of transmitted/founder viruses with their known established phenotypic properties of two times as much Env with an increase (on average, double) of Env trimer spikes per virion particle [14]. If the inactivation of transmitted/founder viruses can be successfully accomplished, the next logical step would be to demonstrate safety and immunogenicity (generation of transmitted/founder viruses neutralizing antibodies) in nonhuman primates. Should a killed transmitted/founder HIV virus vaccine be brought to human clinical experimentation, we suggest using the same immunogenicity assays used in the HIV vaccine trial that has shown some degree of vaccine efficacy, namely the RV144 vaccine trial conducted in Thailand [26]. Such tests can include the use of validated assays such as IFN-υ enzyme-linked immunospot assay and CD4+ and CD8+ intracellular cytokine staining for IFN-υ and interleukin-2 to Gag and Env; binding antibody to gp120 and p24 Gag; lymphoproliferation to gp120 and p24 and antibodies against the V1/V2 region [26,27]. Considering the current status of HIV vaccine development, we believe there is sufficient justification to fully explore the ‘killed’ (inactivation) approach in the development of a preventive HIV vaccine. Acknowledgements Conflicts of interest A.R. and D.W.A. are stock owners of PhotoImmune Biotechnology Inc." @default.
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• W2072675622 title "HIV inactivation" @default.
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