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Despite nearly 30 years of medical science and over 25 million worldwide deaths, why do we still not have a vaccine to HIV?

Introduction

It is because of the complex nature of the human immunodeficiency virus (HIV) that it is able to successfully avoid the host immune system and subsequently destroy it. The fact that after 30 years of research there is still no vaccine for this virus is a clear indicator of how well evolved HIV is. How do you prime an immune system which, even when competent, seems unable to control HIV infection? The first logical approach taken in the development of a vaccine to HIV used methods which have already proven successful in the vaccination of measles, mumps, poliomyelitis, rubella, typhoid and yellow fever. These traditional vaccines include live attenuated virus, inactivated viruses and recombinant protein vaccines (Letvin, 2004). None of these approaches have turned out to be safe or efficient in protection against HIV. This has led to the development of new vaccine strategies which may prove useful in the struggle to find a vaccine for this seemingly unstoppable epidemic.

HIV

In order to create a vaccine it is important to understand the biology of a virus. HIV belongs to the genus lentivirus in the family Retroviridae. So far two types of the virus have been identified: HIV-1 and HIV-2. HIV-1 is the more virulent of the two subtypes and is responsible for most of the cases of AIDS throughout the world. HIV-2 is less virulent and is mostly responsible for AIDS in Western Africa (Montagnier, 2010). HIV-1 is thought to be phylogenetically related to SIVcpz, a commensal virus in chimpanzees, and most likely originated from a single transmission event between humans and chimpanzees (Gao et al, 1999).

The virus is transmitted both venerually and hematoeneously and can be transmitted as a cell free or a cell associated virus (Letvin, 2002). The replication of HIV relies on an active reverse transcriptase which often produces mutant virons, resulting in a genetically heterogeneous population of virons with in one infected individual (Girard et al, 2006 and Letvin, 2002).   The transcription error of this reverse transcriptase may reach about 1 in 100,000 nucleotides which is far greater than that of cellular DNA polymerases which have an error of about 1 in 1,000,000,000 nucleotides (Montagnier, 2010). The genome of the HIV virus is a single stranded RNA molecule about 9,500 nucleotides long (Goldstein, 1996). Given that as may as a billion virons can be produced in one day shows the incredible genetic variability in a population of virons contained with in one infected individual. Remarkably this variability can be further enhanced in some individuals, particularly in Africa, by a secondary infection of a different HIV subtype creating a recombinant of two HIV subtypes. These new recombinants are known as a mosaic virus (Montagnier, 2010). These mosaic viruses have a greater selective advantage over individual HIV subtypes which facilitates their successful transmission into the surrounding population.

The main target of HIV is CD4+ T cells and infection of CD4+ T cells by HIV results in the depletion of CD4+ T cells and leads to acquired immunodeficiency syndrome (AIDS). The virus attaches to the CD4 receptor by the means of an envelope glycoprotein (Env). The Env is a heterodimer of the transmembrane glycoprotein (gp40) and a surface glycoprotein, (gp 120) and forms a trimer on the surface of the viral membrane commonly referred to as spikes. Gp 120 binds to the CD4 receptor on the helper T cell and this binding causes a conformational change in gp120 (Dalgleish et al, 1984 and Klatzmann et al, 1984). The conformational change exposes a co-receptor on the Env (CCR5) which is crucial in the successful binding and integration of the virus and its target cell (Jones et al, 1998). Once infection occurs it is improbable that HIV will ever be fully eliminated from an individual. Clearance of the virus is so difficult because the virus has the ability to integrate as latent proviral DNA into the genome of long lived memory CD4+ T cells creating a persistent reservoir of the virus which avoids detection by the host immune system (Funsi et al, 1999; Blankson et al, 2002; Peterlin et al, 2003).  HIV can avoid detection by the host immune response by downregulating the major histocompatability complex (MHC) class 1 and 2 molecules which allows it to evade detection by cytotoxic lymphocytes (Evans et al, 2001; O’Connor et al, 2001). The protein found to be responsible for this downregulation of MHC class 1 and 2 molecules is nef (Clements et al, 1995).

Live Attenuated Vaccines

Live attenuated vaccines involve the manipulation of a virus in order to lower its virulence but allow it to remain infectious. These live attenuated viruses provide a powerful immune stimulus whilst remaining harmless to immune competent individuals. At first this approach seemed successful when it was tested on rhesus monkeys, the popular primate model for the testing of HIV vaccine strategies, infected with SIV and SHIV. SHIV is a man made virus which expresses HIV envelopes on an SIV backbone (Letvin, 2004). Rhesus monkeys were vaccinated with SIVmac239∆3, an attenuated form of SIV missing the nef protein, and then subsequently challenged with SHIV and SIV strains (Wyand et al, 1999).  Wyand et al (1999) found that vaccination with SIVmac239∆3 was sufficient to prevent rapid CD4+ T cell decline in monkeys challenged with SHIV 89.6p, an aggressive SHIV strain (Fig 1). Although previous studies (Bogers et al, 1995; Cranage et al, 1997) had already shown that vaccination can provide protection against SHIV the strains used in these studies were less virulent forms of SHIV. These results show that vaccination does elicit some protection, although not sterilizing, and emphasized the importance of a CTL response in preventing the rapid decline in CD4+ T cells caused by SHIV infection.

The results of Wyand et al’s study suggested that live attenuated vaccines may be worth pursuing given there ability to prevent rapid CD4+ decline. However later studies using rhesus monkeys by Hofmann-Lehmann (2003) and various others have shown that adult and infant rhesus monkeys vaccinated with SIVmac239∆3 go on to develop AIDS after several years. It was even found that the attenuated strains of SIV had restored the deleted nef gene, although some restored genes were truncated (Hofmann-Lehmann, 2003). This restoration of the nef gene could explain the ability of the SIVmac239∆3 vaccine to restore or regain the ability to cause AIDS in adult rhesus monkeys. These findings called into question the safety of using live attenuated viruses as a vaccine.  However the study by Wyand et al (1999) has shown the importance of a CTL immune response to prevent a rapid decline of CD4+ T cells when infected with SHIV 89.6p.

Inactivated Virus Vaccine

Inactivated viruses have proved successful in vaccination against the influenza and polio viruses but do not seem promising as a vaccine for HIV. Inactivated viruses have been shown to provide protection against macaques infected with a SIV strain identical to the virus used to create the vaccine (Letvin 2002). However protection has proved to be neither broad nor robust in the Macaque/SIV model (Letvin, 2002). Protection has not been shown in this model when the challenge virus and vaccine virus are genetically dissimilar (Letvin, 2002). Another problem with inactivated vaccines is that an inactive virus will not carry out protein synthesis in CD4+ T cells. Thus no CTL response will be induced (Letvin, 2002). Since the genetic variation of HIV is so extreme during the course of infection it is unlikely that an inactivated virus vaccine will prove useful as a possible vaccine strategy, especially since there is no stimulus for a CTL response.

DNA Recombinant Vaccine

This method of vaccination has proved useful as an immunogen for preventing hepatitis B.  However when recombinant HIV envelope glycoproteins were used as an immunogen in the SIV/Macaque model the animals produced neutralizing antibodies but these antibodies were only successful if the challenge virus strain was the same as the envelope gylcoproteins (Levine et al, 1996). This vaccination strategy does not have the variability required to protect against a continuously mutating HIV infection.  DNA recombinant vaccination does not induce a CTL response either which is required to prevent the rapid decline of CD4+ T cells (Letvin, 2002). From these studies it is clear that traditional vaccine strategies do not prove useful in protecting individuals from HIV infection.

BNAbs

In order for antibodies to be successful in neutralizing the HIV virus they must be able to bind consistently to all virons regardless of their genetic differences. The trimeric env or trimeric spike of HIV is a very unstable and compact protein covered in a glycan shield. As explained earlier these spikes are essential to the binding of HIV to CD4+ T cells and are therefore an obvious target for neutralization by antibody binding. The spike has few conserved regions which remain intact throughout the constant variability in the replication and binding of this virus. It is these conserved regions which are most likely to be successful targets for neutralizing antibodies. BNAbs have been described already in infected individuals (Binley et al., 2008; Dhillon et al., 2007; Li et al., 2009). Of these BNAbs there are 4 specific antibodies which have already been well studied B12, 2G12, 2FS and 4E10 (Burton et al.,1994; Muster et al., 1993; Stiegler et al., 2001; Trkola et al., 1995). It has been suggested that just binding to spikes is sufficient for neutralization of the virus, regardless of where. (Zanneti et al, 2006). However there is one problem to be overcome in this approach, vaccination works by exposing the host immune system to immunogens which elicit the production of protective antibodies but in the case of BNAbs the situation is much more difficult. There are antibodies which can successfully neutralize the virus that have already been identified. The main challenge in this case is to indentify immunogens that can elicit the production of these antibodies. Successfully carrying out this process relies heavily on retrovaccinology. This process seeks to understand the interaction between a virus and antibodies to create epitopes that would act as immunogens to elicit the production of the desired BNAb. So far the structure of B12 has been determined (Binley, 2008) so now it remains to create an epitope which will bind well to B12, and use this to be able to create an epitope capable of acting as an immunogen. Another antibody that has had its structure determined is 2G12. This antibody binds to sugars in the glycan shield and if these sugars were to be identified and their orientation determined this would allow an epitope to be created which could elicit the production of the 2G12 antibody (Calarese et al, 2003). Retrovaccinology could prove useful in the development of a vaccine for HIV. However the results are still to be determined and the one problem with this approach is that it would only prove useful in neutralizing a cell free virus.

Live recombinant vaccines

These vaccines work by transferring the RNA of HIV into a less virulent virus which can replicate using this RNA and induce a HIV CTL response. One of the set backs of this approach is an existing immunity to the virus being used as a live vector. The most successful candidates for this approach are the measles virus, Sendai virus (SV) and the Venezuelan equine encephalitis virus (VEEV) (Girard et al, 2006). The attenuated MV strain has proved to be safe and expresses the gp160 envelope glycoprotein. This live vector has been shown to elicit the production of BNAbs in mice (Lorin et al, 2004). The VSV vector has been tested in the SHIV/ Macaque model. In this test macaques had low or undetectable virus loads for 14 months after a challenge (Rose et al, 2001). This vector has been shown to elicit the production of antibodies as well as a memory CTL response in mice (Publicover et al, 2008). The VEEV vector has also proved successful in primates inducing a potent and protective immune response (Perri et al, 2003). All of these vectors show promise as potential HIV vaccines, especially VSV and VEEV. The main goal now is to successfully show there is a potential for the vaccination of humans.

Conclusion

It is clear that traditional methods of vaccination are not useful as vaccines for HIV. However there has been significant progress in the development of new vaccines which have shown promise as potential vaccination candidates in the SHIV/Macaque model and in other small mammals. It is clear that a successful vaccine would elicit the production of BNAb and also induced a response of HIV specific CTLs. Something which the live vector VSV has been shown to be capable of. So after 30 years there may still be no vaccine but retrovirology and particularly live recombinant vaccines look promising as future prospects for the vaccination of HIV.

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