Challenges for HIV Vaccine Design

The history of successful immunization dates back to the time of Jenner, whose success with a smallpox vaccine in 1796 was achieved with little understanding of the actual mechanisms of protection that were being induced. By mimicking infection with smallpox by inducing a benign cowpox infection, Jenner laid the foundation for modern vaccinology. Most vaccines currently in use, if not all, do not actually prevent infection, but rather attenuate disease caused by the pathogen. In fact, most mimic something that happens naturally – namely that some fraction of people who become infected clear their infections (Walker, 2008)

The situation with HIV is quite different as HIV is an infection in which, to our knowledge, spontaneous clearance never occurs. The natural history of HIVinfection is one of progressive viremia, in which the targets of the virus are cells of the immune system itself, particularly CD4 + T-lymphocytes. Following infection, there is a gradual decline in CD4 + cell number and an increase in viral load, typically resulting in AIDS within 8–10 years, which is defined by a CD4 + cell count of less than 200 or specific AIDS-defining illnesses. HIV is actually an infection of the immune system, with CD4 + T-lymphocytes being a key target of the virus, which enters these cells through its coreceptors CCR5 (or occasionally other chemokine coreceptors such as CXCR4) and CD4.

There are five main properties of HIV that render the development of an HIV vaccine an unprecedented challenge.

1.    Massive infection of immune cells: HIVuses its envelope protein to gain access to cells bearing its coreceptors, CD4 and the chemokine receptor CCR5 or CXCR4. The major target of the infection are CD4 + T-cells, and because activated cells are preferentially infected by HIV, the infection preferentially appears to deplete HIV-specific CD4 + cells. The infection of CD4 + cells is massive at the acute stage of infection, when up to 60% of CD4 + T-cells in the gut-associated lymphoid tissue (GALT) are depleted (Brenchley, 2004).

2.    Integration into the host chromosome: HIV is a retrovirus, and following viral entry the viral reverse transcriptase initiates the production of a double-stranded proviral DNA that can remain as free circular DNA and undergo processes of transcription and translation to make new virion particles. Alternatively, it can use the viral integrase protein to create a nick in the host chromosome, and integrate. Once integration occurs – which all indications suggest happens very early after acute infection (Finzi, 1999) – the virus can remain in an immunologically latent state. This is possible because the lack of transcription and translation of viral proteins means that the normal immune mechanisms, which rely on the detection of foreign viral protein within cells to induce immune attack, do not occur.

3.    Viral diversity: HIV is a retrovirus, and viral replication is dependent on an errorprone viral reverse transcriptase that has a poor proofreading function. As a result, with each replication cycle there is likely to be at least one nucleotide misincorporation. At least some of this diversity is driven by immune selection pressure, which has been shown to be progressively deleting some key epitopes of the virus at a population level (Kawashima, 2009). Globally there are three main groups of HIV– M, N, and O – with group M (the largest) being further divided into nine distinct clades and additional circulating recombinant forms. Viruses within a clade may differ by up to 20% in the highly variable Env protein, which is the target for neutralizing antibodies, and by up to 38% between clades. Even within a single individual HIV mutates such that individuals carry unique strains. Developing a vaccine to target all of these viruses simultaneously is an enormous task.

4.    Envelope glycosylation: The HIV envelope is heavily glycosylated, and also very flexible, in that it allows for a high degree of random mutations to be stably incorporated. This combination of Env variability, together with heavy glycosylation that renders key epitopes poorly exposed to antibody-mediated immune attack, has been a major challenge for any vaccine to provide broad crossneutralizing protective antibody responses (for a review, see Ref) (Walker, 2008). Indeed, at the current time this is such a challenge that many in the field have focused not on a preventive HIV vaccine – which would require the induction of broadly crossreactive neutralizing antibodies – but rather on a T-cell-based vaccine which would be intended to provide a durable reduction in viral load, and thereby retard disease progression and reduce the likelihood of transmission to others (Barouch, 2008).

5.    Immune evasion: The HIV accessory protein Nef interacts indirectly with the cytoplasmic tail of HLA A and B alleles, leading to endocytosis and a downregulation of class I expression on infected cells (Scwartz, 1996). This impairs the ability of cytotoxic T lymphocytes to recognize infected cells, and has been shown to have functional significance on the ability to contain HIV replication (Collins, 1998). Neutralizing antibodies are unable to recognize the variants that arise in vivo (Finzi, 2008 ; Wei, 2003 ; Richman, 2003), so that the humoral immune response is always playing catch-up. In addition, mutations arising within targeted CD8 + T-cell epitopes also lead to either a loss of recognition by the T-cell receptor (TCR) of established responses, or to a loss of binding of the epitope to HLA class I, allowing immune escape.

Source  :       Aids and Tuberculosis : A Deadly Liaison

                     (Edited by Stefan H. E. Kaufmann and Bruce D. Walker)


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