December 2007 Vol 8 After Meeting.indd SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL DECEMBER 2007 VOL 7, NO. 3, P. 193-195 SULTAN QABOOS UNIVERSITY© SUBMITTED - 11TH SEPTEMBER 2007 ACCEPTED - 30TH SEPTEMBER 2007 HIV/AIDS Vaccines How long must humanity wait? Ali A Al-Jabri OVER FORTY MILLION PEOPLE ARE INFECTED with the human immunodeficiency virus(HIV), the causative agent of acquired im- munodeficiency syndrome (AIDS), and more than 95% of these infected individuals are in the developing countries. The prevalence levels for this virus will con- tinue to rise globally. The HIV/AIDS pandemic is the most devastating global public health crisis since the great plagues of the middle-ages with approximately fifteen thousand new HIV infections and ten thousand deaths due to AIDS every day and approximately 3.1 million total deaths due to AIDS.1 Historically, vaccines have proven to be the most effective weapon in our fight against infectious diseases such as small pox, po- lio, measles and yellow fever. HIV vaccines are our best hope to end the HIV pandemic. Although successful vaccines have been developed for the common child- hood diseases, the development of a vaccine against the AIDS virus is a much greater challenge. The best way to stop the spread of the disease and the suffering of AIDS patients is by the development of successful vaccines to prevent infection with HIV and delay or stop progression to AIDS. It is now two dec- ades and a half since HIV was first discovered and re- searchers have spent millions of Riyals (Omani curren- cy; 1 Riyal = 2.6 US$) looking for possible candidates as vaccines, but what is the outcome of this research? It seems the discovery of a licensed and globally acces- sible HIV/AIDS vaccine is still years away, the question that arises is: how soon are we going to see a success- ful HIV/AIDS vaccine? More realistically, how long are we going to wait for such a vaccine? In this article, I will very briefly touch on the scientific hurdles that have impeded the search for an effective AIDS vaccine and discuss novel research approaches to accelerate its progress. Despite important progression in the understand- ing of HIV pathogenesis2 and HIV/AIDS virus com- pared to any other viral disease, why are we still not able to produce an effective or even partially effective HIV/AIDS vaccine? The answer to this question lies in understanding how the virus evades the immune sys- tem. First, HIV disables the very cells that are respon- sible for fighting it. Second, HIV is able to integrate its viral genome into the chromosome of the infected cells and therefore hide from recognition by the im- mune response for many years. Third, HIV is able to conceal the protein components that can induce pro- tective immune responses and therefore presents itself to the body in a way that makes it difficult for the im- mune system to respond effectively. Fourth, HIV is ge- netically diverse and rapidly changing, particularly its outer envelope, and this allows the virus to evade most of the natural and protective immune mechanisms that the immune system is able to make. As soon as HIV infection becomes established, HIV continues to mu- Department of Microbiology & Immunology, College of Medicine & Health Sciences, Sultan Qaboos University, P.O. Box 35, Al-Khod 123, Muscat, Sultanate of Oman. Email: aaljabri@squ.edu.om E D I T O R I A L (االيدز) املناعة املكتسبة نقص ومتالزمة فيروس ضد اللقاحات تنتظر؟ أن البشرية على يجب الوقت من كم اهللا اجلابري عبد بن علي A L I A . A L - J A B R I 194 tate genetically and many variants may arise within an infected person. Therefore, investigators need to know the significance of strain variation within the individu- als and among the populations when developing an ef- fective HIV/AIDS vaccine. The most logical approach for designing an effec- tive HIV/AIDS vaccine is to identify which immune responses are most protective against this virus infec- tion and to construct a vaccine that is able to stimulate these protective responses. Of the two main types of immune responses, the humoral immune response mainly uses antibodies to protect against a cell-free virus, whereas the cell mediated immune response is essential for body defense when the virus is hidden inside the cells. Although earlier vaccine research fo- cused primarily on vaccines that elicited antibodies, it is now generally believed that both arms of the im- mune response are required in order to control and prevent HIV infection. Moreover, much attention has recently been directed towards vaccines that induce good innate (natural) immune responses particularly dendritic cells and toll-like receptors which play an important role in inducing and modulating the adop- tive immune responses.3 The most practical goal for an HIV vaccine is to prevent HIV transmission rather than preventing in- fection with the virus. Experts believe a vaccine is the only way to eradicate HIV/AIDS because the most common modes of transmission, sexual contact, in- jection drug use and mother-to-child transmission at childbirth or breast-feeding are impossible to elimi- nate completely. The main characteristics of a desir- able HIV vaccine are: safety, simple administration as well as affordable cost, long lasting immunity and ef- fective against all HIV subtypes. To develop such an HIV/AIDS vaccine there is a need for team work in fundamental basic research; preclinical screening for active candidates and appropriate animal model fol- lowed by product development, manufacturing, and clinical research.3 Currently, there are more promising vaccine can- didates being tested than ever before. Vaccine can- didates are being constructed based on isolates from different regions of the world, and several research groups are testing a cocktail or a mixture of different viral components from different isolates of HIV. In ad- dition, to optimize the immune responses, new vac- cine strategies are being tested [Table 1]. The most current HIV vaccine candidates focus on producing cytotoxic CD4+ T cells, which attack HIV- infected cells in the body; such vaccines might not prevent an HIV-negative person from contracting the virus, but would delay HIV from progressing to AIDS and prevent transmission to others. Another challenge in vaccine research is that HIV strains vary among people and regions. Vaccine trial participants are cho- sen based on health standards for industrialized na- tions and many people in developing countries are not healthy enough to participate in such trials.4 Vaccine- induced antibodies that interfere with viral entry are the protective correlate of most existing prophylactic vaccines; however, for highly variable viruses such as HIV-1, the ability to elicit broadly neutralizing anti- body responses through vaccination has proven to be extremely difficult. The major targets for HIV-1 neu- tralizing antibodies are the viral envelope glycoprotein trimers on the surface of the virus that mediate recep- tor binding and virus entry. HIV-1 has evolved many mechanisms on the surface of envelope glycoproteins to evade antibody-mediated neutralization, including Subunit vaccines (a structural piece of HIV such as the envelope or a core protein) Live vector vaccines (a live bacterium or virus modified to carry genes that encode HIV proteins). Peptides (small pieces of HIV proteins). Fusion protein vaccines (two proteins merged together). DNA vaccines (direct injection of HIV-DNA sequences). Vaccine combinations such as the prime-boost strategy Table 1: Examples of HIV vaccine strategies H I V / A I D S VA C C I N E S 195 the masking of conserved regions by glycan, quater- nary protein interactions and the presence of immu- nodominant variable elements. The primary challenge in the development of an HIV-1 vaccine that elicits broadly neutralizing antibodies therefore lies in the design of suitable envelope glycoprotein immunogens that circumvent these barriers.5 Individuals who are infected with HIV but remain healthy and keep viral replication in check may offer some hope for guiding the design of an effective HIV vaccine.6 Some of these long-term survivors make a very small amount of antibody, which, when isolated, can neutralize HIV from patient isolates. Further, those antibodies can neutralize viruses from many dif- ferent patient isolates, which is necessary for an AIDS vaccine that will be effective against a broad spectrum of HIV strains. Unfortunately, even these antibodies may not be the whole answer. Tests of cells in culture indicate that the antibodies must be present at sur- prisingly high concentrations to block HIV entry into cells effectively. Many researchers continue to look into developing a live, attenuated HIV vaccine despite safety concerns. Because such a vaccine would closely mimic active HIV, it should theoretically be effective at inducing cellular immunity, antibody-based immunity and per- haps-other unknown modes of protection. By system- atically deleting genes critical for HIV replication, sci- entists hope to develop a variant of the virus that can elicit a strong immune response without giving rise to AIDS.4 It also is hoped that vaccines may give the body an immunological ‘head start’ by priming the immune system to attack HIV as soon as it appears, rather than taking time to initiate a defense from scratch. As the pathogenesis of HIV infection has be- come better understood, investigators have realized that if the virus can be kept at low concentrations in the blood, an infected person may never progress to AIDS.7 This insight is encouraging because it suggests that even a partially effective vaccine could be valuable in limiting the amount of virus in patients, thus po- tentially reducing virus infectiousness and the AIDS symptoms. The multitude of scientists searching for success- ful AIDS vaccines will require appropriate funding and ample time. Funding is now improving, but be- cause of the above difficulties we may not see a vac- cine in near future.8 Governments need to cooperate to break barriers, reduce the stigma associated with HIV/AIDS, encourage HIV testing, provide support for people with HIV/AIDS and allocate appropriate funding to institutes that work for the development of HIV/AIDS vaccines. The development of appropri- ate antiviral therapy and reconstructing the damaged immune system are two approaches, both of which require significant financial support. For developing countries, educating the public on preventative meas- ures is the first step in preventing and reducing the spread of HIV/AIDS. Treating those infected with HIV or who have AIDS is also, of course, critical, but the real hope for the future lies in developing a suc- cessful vaccine. R E F E R E N C E S 1. WHO. Report on global AIDS. 2006. 2. Sailaja G, Skountzou I, Quan FS, Compans RW, Kang SM. Human immunodeficiency virus-like particles ac- tivate multiple types of immune cells. Virology 2007; 362:331-341. 3. Kwissa M, Villinger F, Amara, RR, Alkan S, Robinson H, Jabbar A, et al. Harnessing dendritic cells and TLR ligands to enhance the immunogenicity of a plasmid DNA/rMVA prime boost vaccine against SIV in Rhesus Macaques. 13th International Congress of Immunol- ogy, Rio de Janerio, Brazil, Aug 21-25, 2007. MS-71.1. 4. The Jordon Report. Accelerated development of vac- cines. National Institues of Health 2007. NIH Publica- tion No. 06-6057. http://www.cdc.gov-vaccines-recs- acip-downloads-mtg-slides-jun07/37-jordanrpt-curlin. pdf. Accessed Sept 2007. 5. Phogat S, Wyatt RT, Karlsson Hedestam GB. Inhibition of HIV-1 entry by antibodies: potential viral and cellular targets. J Intern Med 2007; 262:26-43. 6. Al-Jabri AA. Mechanisms of host resistance against HIV infection and progression to AIDS. Sultan Qaboos University Medical Journal 2007; 7:13-26. 7. Rodríguez B, Sethi AK, Cheruvu VK, et al. Predictive value of plasma HIV RNA level on rate of CD4 T- cell decline in untreated HIV infection. JAMA 2006; 296:1498-506. 8. Day M. AIDS expert doubts vaccine will be found in near future. BMJ 2007; 334:1133.