The immunopathogenesis of HIV disease

Professor Frances Gotch Msc PhD MRCPath Department of Immunology, Imperial College of Science, Technology and Medicine, Chelsea & Westminster Hospital, London

The T-cell surface antigen CD4 is the principle binding site for the HIV virus, but alone it is insufficient to allow entry of virus into the cell. Now, however, HIV coreceptors have been identified: seven transmembrane G-protein coupled receptors.

CCR2b, CCR3 and CCR5 are coreceptors that are permissive for macrophage tropic viruses, which predominate in early infection. CXCR4 (fusin) is a receptor that is permissive for T-cell trophic strains, which predominate in late infection. Coreceptors may be blocked with chemokines and, in particular, CCR5 may be blocked with MIP1alpha, MIP1beta or RANTES.

A 32 basepair deletion from the coding region of CCR5 results in a frame shift, and the gene product is a non-functional receptor. Individuals who are homozygous for this deletion have been shown to be resistant to infection with HIV, and individuals heterozygous for the mutation progress to AIDS more slowly than patients without the mutation. The protective allele is absent in black populations and in populations from Japan.

Initial activity

Immediately following infection with HIV there is a burst in virus replication with levels as high as 10 6 RNA copies/ml being detected in some patients. This viraemia peaks after 4-8 weeks from the onset of symptoms and then usually drops by many logs, to sometimes undetectable levels, even without treatment with antiretroviral drugs. High viral RNA levels at the time of seroconversion are prognostic of a rapid disease progression. Such non-clearance of virus implies that the immune system is not working well, which may be due to host (genetic) factors, such as HLA type or second receptor usage, or to viral factors - some viruses being more pathogenic or less immunogenic than others.

Infection with HIV results in:
The immune response is able to contain virus infection (there is a very high viral turnover with up to 10 9 virions being generated each day) but cannot control viral replication completely.

Virus specific CD8+ CTL are induced before seroconversion, and often before viral RNA has reached peak titres, and they are temporally associated with the fall in viraemia during acute infection. In most viral infections that have been studied CTL represent the major weapon in controlling viral growth.

Asymptomatic phase

During the asyptomatic phase of HIV disease the immune response (both humoral and cellular) continues to contain viral replication. CD4 counts remain high and viral load is low. However, the virus is able to evade immune surveillance. It does this by:

Symptomatic phase

During the symptomatic phase of the disease (AIDS) there is often a switch in viral phenotype from non-syncitium-inducing (NSI) virus to syncitium-inducing (SI) virus. Chemokines produced by activated T-cells cannot block the entry of SI viruses into CD4 cells.

There is a decline in immune competence, reflected by a decrease in the numbers of CD4 cells, which fall to >200/mm 3 in AIDS. The decline in immunocompetence could be due in part to HIV in lymphoid foci. This is able to impair CTL responses by increased concentrated production of immunosuppressive viral proteins.

There is rapid emergence and replication of `escape' viruses, which unbalance the set point between the immune response and virus growth.

Generalised decline in immunocompetence leads to the emergence of opportunistic infections, growth of tumours and finally to death.

A healthy immune response is the best weapon against HIV

The immunological effects of highly active antiretroviral therapy (HAART) are being investigated. These effects include:

Improvements in immune function are most evident when the immune system has some measurement of function before therapy. There is no data showing that present treatments for HIV can completely restore lost immunological function, and it is likely that immune reconstitution will take a considerable time. Modulation of the immune response to HIV during triple therapy (using, for example, therapeutic vaccines or cytokines), may help to prevent therapeutic failure and aid the removal of virus from the body.