Summary of CDC 1992 classification system for HIV disease

Group I        Primary HIV
Group II     Asymptomatic infection
Group III    Persistent generalised lymphadenopathy
Group IV     Symptomatic infection
Group IVA   HIV wasting syndrome (AIDS) and constitutional disease
Group IVB   HIV encephalopathy (AIDS) and neurological disease
Group IVC1 Major opportunistic infections specified as AIDSdefining
Group IVC2 Minor opportunistic infections
Group IVD  Cancers specified as AIDS-defining
Group IVE   Other conditions

Possibilities for immunotherapy

        Attempts at immune reconstitution have been made using interleukin 2, interferons, thymic factors or bone marrow transplantation.

        These have not been notably successful and remain potentially harmful, since the very factors which activate T-cells will also activate HIV replication. In vivo, activation of CD4 cells is caused by stimulation with antigens in the form of micro-organisms or vaccines.

      This suggests that it is sensible to treat intercurrent infections promptly and provides a rationale for prophylactic chemotherapy for pneumocystis. In some studies, vaccination (for example with influenza vaccine) has been shown to be enough of an antigenic stimulus to increase HIV replication. The advent of highly activated antiretroviral therapy (HAART) has enabled the viral load to be enormously reduced, but the difficulty of maintaining this type of therapy over long periods has led to a search for strategies to complement drug treatment.

      Two observations are pertinent, the first is that even after 2–3 years of HAART treatment, latent virus can still be detected and the second is that antiviral immune responses decline during treatment. It has therefore been suggested first that latent virus should be “flushed out” by activation of the immune system with anti-CD3 antibody or interleukin 2 while still continuing drug treatment. Secondly vaccination against HIV should be instituted to prevent recrudescence of low level infection. Both strategies are being actively investigated.

Strategies for vaccine development

• A good vaccine should induce neutralising antibody, helper T-cells and cytotoxic T-cells.

• Since antibodies bind to three dimensional structures, induction of neutralising antibody requires native envelope.
Problem: Native envelope is trimeric.

 • T-cells recognise 8–15 amino acid-long peptides bound to Major Histocompatibility Complex (MHC) class I and II molecules.
Problem: Antigen needs to enter antigen presenting cells, usually dendritic cells, to be broken down to peptides.

• Peptides with novel adjuvants can generate good T-cell responses.
 Problem: Different peptides bind to each MHC allele so a large cocktail of different peptides may be needed.

 • Adjuvants are needed to induce large responses.
Problem: There are very few adjuvants available for unrestricted use in humans. Alum is mainly good for induction of antibody responses.

• DNA immunisation can generate antibody, helper and cytotoxic responses and allows incorporation of adjuvant molecules into the vaccine. Problem: So far DNA vaccination has not proved as effective in man as in experimental animals.

• HIV is very variable and escape variants arise rapidly in infected individuals. Prophylactic immunisation may tip the balance in favour of the host and prevent escape. Some parts of the virus sequence are relatively invariant, these should be targeted if possible.

• In experimental animals immunisation with different immunogens appears promising. DNA vaccination followed by immunisation with antigen in a recombinant viral vector seems particularly effective. This is now under trial in man.

Vaccine development

          Immunisation against an organism whose target is an important component of the immune system presents particular difficulties.
         In addition, HIV has already been shown to be perhaps the most variable virus yet discovered, and HIV-2 differs greatly from all HIV-1 isolates. So far, efforts to immunise against the virus have concentrated on the use of cloned gp120 because all strains of virus so far tested use gp120 to bind to the CD4 molecule, implying that a part of the envelope is similar in all strains. In experimental animals gp120 does induce a neutralising antibody response to the virus but restricted to the immunising strain of virus (type specific immunity) and these neutralising sera do not provide reliable protection against virus challenge in vivo in animal experiments. More recently it has been shown that gp120 and its anchor gp41 exist in the viral envelope as a trimer of heterodimers. Because of this and because gp120 is heavily glycosylated, much of the antibody response is to the variable V2 and V3 loops. Furthermore, primary isolates have been shown to be less susceptible to neutralisation than the tissue culture-adapted strains, from which the recombinant gp120 used as immunogen in most experiments derives. Thus new immunogens are needed to raise broadly reactive neutralising antibody and a variety of oligomeric and deglycosylated forms of gp120, lacking the V2 and V3 loops, are being tried.

        High levels of CTL are seen in the early stages of HIV infection and the demonstration of CTL escape mutants suggests that they play a role in controlling the virus. That individuals exposed to HIV but with no evidence of infection exhibit CTL responses, reinforces the view that this type of response is important in protection. An effective vaccine might therefore contain components able to stimulate both neutralising antibody, CD4 T-cells and strong CTL responses.

     A key factor in generating immune responses is the way in which the antigens are presented to the immune system. For the generation of effective CTL responses attenuated live viruses are effective and attenuated (nef deleted) simian immunodeficiency virus (SIV) has been shown able to protect monkeys against challenge with virulent virus. While such a strategy is unlikely to be used in humans because of worries about the safety of such a virus, it suggests that live viral vectors may be an effective means of immunising against HIV. HIV genes have been inserted into several possible vectors (vaccinia, canary pox, adenovirus) and a number of phase 1 trials are in progress. Alternate means of delivery capable of inducing both antibody and cellular immunity, such as peptides or proteins in novel adjuvants, naked DNA, or the use of different methods of antigen administration in sequence (prime/boost regimes) are under active investigation.

Causes of CD4 lymphopenia

• HIV infection: seroconversion illness and during disease progression • Acute viral infections* • Tuberculosis* • Sarcoidosis* • Corticosteroid therapy • Purine metabolism defects; ADA and PNP deficiency • SLE * Reduce CD4 counts when not associated with HIV and can further reduce levels in HIV infection. ADA, Adenosine deaminase; PNP, Putine nucleoside phosphorylase