The net loss of CD4 T-cells that develops during HIV infection has many direct and indirect consequences during HIV infection. There is less response by CD4 T-cells to antigens and less production of some cytokines. There is less response by CD8 T-cells to virus- and bacteria-infected cells. CD4 memory T-cells are lost so that the more efficient responses of acquired immunity decrease against familiar micro-organisms.

Memory B-cells excessively produce a wide range of antibodies against previously encountered antigens but there is an impaired response to new antigens. B-cells may not function normally. Natural killer cells have less activity against virus-infected cells because of cytokine abnormalities.

CD8 T-cells

CD8 T-cells have been shown to express CD4 receptors on their surface after activation through the T-cell receptor. Expression of the CD4 molecule permits infection by HIV. Robert Gallo and colleagues have demonstrated that CD8 T-cells can become infected in the laboratory, and have proposed that this is the mechanism by which CD8 T-cells become depleted in HIV infection, leading eventually to the exhaustion of HIV-specific CD8 T-cells and the loss of immunological control over HIV.

Other researchers have proposed an alternative mechanism for CD8 T-cell depletion, in which HIV-specific T-helper cells play the key role. CD4 T-helper cells specifically targeted at HIV emerge during primary infection, but many of these cells are probably infected and killed by HIV rapidly, precisely because of their activation in the presence of HIV. This activation offers new targets for infection.

CD4 T-helper cells activate CD8 T-cells, and strong CD4 T-helper cell and CD8 T-cell responses have been shown to correlate with long-term non-progression in several cohorts. It has been suggested that restoring the HIV-specific CD4 T-helper response by the use of a therapeutic vaccine would contribute to suppression of HIV and maintenance of a strong CD8 T-cell response to HIV.

Dendritic cells

Follicular dendritic cells in the lymph tissue are a major source and reservoir for HIV. Dendritic cells in lymph nodes are destroyed during HIV infection. It has been shown that dendritic cells can pick up HIV and ingest it, rather like a phagocytic cell. However the dendritic cell usually fails to digest HIV and instead carries it around the body, delivering it to susceptible CD4 T-cells in the lymph nodes. The tight gap between the dendritic cell and the CD4 T cell through which HIV passes has been termed the infectious synapse (McDonald 2002).

Cytokines

There are many long-standing changes to cytokines during HIV infection. IL-6 (interleukin-6) levels are increased and this activates most B-cells to release more of their antibodies, even though the antibodies may not be needed to fight infections all of the time. Elevated levels of a wide range of antibodies in the blood (hypergammaglobulinaemia) are a feature of HIV infection. B-cell activation may be one factor involved in the formation of B-cell non-Hodgkin lymphomas, a type of cancer which is more frequent in HIV infection.

Other cytokine changes also affect immune function.

• Interleukin-2 (IL-2) normally stimulates division of T- and B-cells and the killing of virus-infected cells by natural killer (NK) cells. IL-2 levels decrease in HIV-infection.

• Interferon gamma is also reduced. Normally, interferon gamma inhibits viruses replicating inside cells and stimulates cytotoxic cells.

• Tumour necrosis factor (TNF) is increased and activates T-cells and HIV replication, as well as causing fever, weight loss and a feeling of being unwell. Drugs that may reduce levels of TNF are oxpentifylline and thalidomide.

One theory to explain changes during HIV-infection concerns an apparent shift in the roles of the CD4 T-helper cell subsets known as type-1 (Th1) and type-2 (Th2) cells. Early on, Th1 cells predominate and they are associated with production of IL-2 and interferon gamma and high activity by cytotoxic cells. This may help clear lots of HIV by cell-mediated immunity.

Later, Th2 cells are dominant with production of IL-4, IL-6 and IL-10 which activates B-cells and antibody production. This humoral immunity may be a less efficient at controlling HIV. It may be possible to use synthetic cytokines or drugs to correct these abnormalities and several drug trials are under way to test these as treatments. In recent years more sophisticated technology has failed to confirm a real shift from Th1 cytokines to Th2 cytokines in HIV infection and many Th1 interferon gamma responses are still seen, despite disease progression.

Antibody production

HIV will evade the specific antibodies made against it by varying the structure of its envelope proteins, such as gp120 and gp4. HIV's ability to mutate is one of the fastest rates known amongst viruses.

Early in HIV infection the B-cells may keep up with the new antigens produced but this response is slow or absent in late infection. It is possible that the B-cell response can become exhausted. Direct HIV infection of B-cells may also undermine their functioning. Potential HIV vaccines have been made which mimic parts of gp120 that are the least likely to vary over time.

Lastly, HIV may infect the stem cells in the bone marrow from which immune cells originate, which could interfere with their replacement.

Reference

McDonald D et al. Recruitment of HIV and its receptors to the dendritic cell-T cell junction. Science 300: 1295-1297, 2003.