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lentivirus RNA virus Â a member of theÂ retrovirusÂ family that causesÂ acquired immunodeficiency syndrome (AIDS),Â a condition in humans in which progressive failure of theÂ immune systemÂ allows life-threateningÂ opportunistic infectionsÂ and cancersÂ to thrive. Infection with HIV occurs by body fluids . The four major routes of transmission are : unsafe sex (vagina & semen ), breast milk,needle injection(blood) and finally perinatal transmission. There are 2 types of the virusHIV1 & HIV2 ,HIV1 virus is more common than HIV2. (1).
Why it is important to produce HIV vaccines ?
This is very important in the interruption of chain of transmission of virus, could reach populations where other interventions are not sufficiently effective & providing new information on the possible use of vaccines as therapeutic interventions.(2)
Possible HIV Vaccine Strategies
Experimental vaccines do not use whole or live HIV , cannot cause HIV or AIDS & should produce eitherÂ antibodies orÂ cytotoxic T cells (CTLs)Â to fight infection.(3)
Types of Experimental HIV Vaccines are :
peptide vaccine : composed of tiny proteins from virus
recombinant subunit protein vaccine : made of larger proteins from the surface of the virus
live vector vaccine : the genes encoding HIV are carried by non-HIV viruses
DNA vaccine: small parts of HIV genes inserted to DNA pieces called plasmid
vaccine combination : uses any two vaccines, one after another, to create a stronger immune response
virus-like particle vaccine (pseudovirion vaccine):Â non-infectious HIV look-alike that has one or more, but not all, HIV proteins.(3)
Vaccine trials and researches :
Scientists have made many efforts in order to undrstand mechanisms by which HIV virus resistance in order to produce effective vaccines , such as analysis of gene expression profiles of CD4+ T cells from HIV-1-resistant individuals and HIV-susceptible individuals (4).Depending on analysis of published dataset that included 85 samples from HIV-1-resistant individuals and 50 samples from HIV low-risk negative individuals (5) , 185 HIV-1 resistance genes were identified using Minimum Redundancy-Maximum Relevance (mRMR) and Incremental Feature Selection (IFS) methods. This analysis have showed that HIV1 nef protein plays an important role in virus infection .They found 29 genes from those 185 genes which are located on shortest pathes beween virus-targeted proteins and play an important role in interruption of communication between targeted proteins & virus invasion .SO , they targeted these genes which caused this disruption to use them either in treatment or prevention of AIDS .(4) .
This can be easily related to the studies of athor viruses like H1N1 Influenza virus .(6)
Resules of this expriment were very good. Scientists have identified HIV resistance genes , their biological functions ,relationship between these genes & virus proteins & Network analysis of virus-host interaction . (4)
Other researchers have concentrated on development of veccines that based on T-cells against HIV virus (7) .This strategy of vaccination is useful in limiting of both trasmission and disease progression by controlling HIV viral loads (8).
CD4 T-cells are important in differentiation and maintenance of cytotoxic CD8+Â T cells and B cells . Magnitude and duration of HIV CD4 T-cell mediated response , determines outcome of infection.
They developed DNA vaccine encoding 18 conserved multiple HLA-DR-binding HIV-1 CD4 epitopes (HIVBr18), responsible for iniciating cell mediated immune responses (CD4+Â T) in mice and evaluated responses . This vaccine was able to elicit Â broad CD4+/CD8+Â T cell responses , induction of polyfunctional CD4+Â and CD8+Â T cells in response to HIV-1 peptides , long-lived central and effector memory CD4+Â T cells generation . Thats was crucial in sustained help for CD8+Â T cells and antibody responses- elicited by other HIV immunogens.(7)
Other researches focused in using other viruses to develop HIV vaccines , i.g, using Poxviruses . Although poxviruses are used as candidate human vaccines , they have multiple genes encoding proteins interfere with components of innate and adaptive immune response. Poxviruses express multiple genes encoding proteins that interfere with components of innate and adaptive immune response. Scientists have described two strategies aimed to improve immunogenicity of host-range restricted poxvirus NYVAC :first, deletion of viral gene encoding type- I interferon-binding protein and second , development of attenuated replication-competent NYVAC . They evaluated newly generated NYVAC mutants , encoding HIV-1 Â env ,Â gag ,Â polÂ and Â nef, for their ability to stimulate HIV-specific CD8 T-cell responses Â in HIV-infected subjects. New vectors were evaluated and compared to parental NYVAC vector in dendritic cells (DCs), RNA expression arrays, HIV Â gagÂ expression and cross-presentation assays in vitro. Deletion of type-I interferon-binding protein enhanced expression of interferon and interferon-induced genes in DCs , and increased maturation of infected DCs. Activation of pathways involving antigen processing and presentation is accomplished by restoration of replication competence . Also, replication-competent NYVAC showed increased Gag expression in infected cells, permitting enhanced cross-presentation to HIV-specific CD8 T cells and proliferation of HIV-specific memory CD8 T-cellsÂ in vitro. The recombinant NYVAC combining both modifications induced interferon-induced genes and genes involved in antigen processing and presentation, as well as increased Gag expression. This combined replication-competent NYVAC is a promising candidate for the next generation of HIV vaccines.(9)
Another concepts for development HIV1 vaccines is plasmid-based DNA vaccines .This needs large doses of plasmids to get weak responses. By using genome elements derived from Porcine circovirus type 1 (PCV-1), an apathogenic small ssDNA-containing virus, which showed useful expression-enhancing properties allowed dose-sparing in a plasmid vaccine. resultes were as follows :
linear PCV-1 genome inserted 5' of CMV promoter in the HIV-1 plasmid vaccine pTHgrttnC increased expression of polyantigen up to 2-fold, and iniciated 3-fold higher CTL responses in mice at 10-fold lower doses than unmodified pTHgrttnC . The PCV-1 capsid gene promoter (Pcap) alone was equally effective. Enhancing activity was traced to a putative composite host transcription factor binding site and a "Conserved Late Element" transcription-enhancing sequence previously unidentified in circoviruses This should allow significant dose sparing of, or increased responses to, this and other plasmid-based vaccine .(10)
Design of neutralizing antibody-based vaccines have been also used to prevent HIV-1 transmission, by reversed engineering, starting from a neutralizing antibody and working back to reconstruct its epitope by structure-based design technology. But there was some disadvanteges such as lack of appropriate antibodies for use as templates. New antibodies have been described that may acheive this role recently . (11)
Neutralizing antibodies target Evn glycoprotein of HIV (11).Â Env is a trimer of heterodimers, each of which is composed of a receptor-binding surface glycoprotein (gp120) and a fusogenic transmembrane glycoprotein (gp41), linked together by non-covalent bonds .(12)
Neutralizing monoclonal antibodies (NMAbs), which recognize conformation-dependent epitopes & neutralize wide spectrum of viral strains , are under investigation.
Development of vaccines against HIV virus still a challange for scientists and researchers .Moreover there are additional limitations & difficulties that prevent them from developing effevtive vaccine that prevent the infection completely .