Immunology of  HPV Infection

Prior infection with an oncogenic HPV type does not always provide women with sufficient immunity against subsequent infections or reduce the risk of an HPV infection becoming persistent (de Jong et al 2004; Baseman and Koutsky 2005). Over a lifetime, repeat infections with different HPV types will take place and can regress, however, persistent infection with oncogenic HPV types increases the likelihood of the development and progression of cervical cancer (Bosch et al 1995).

Prior infection with an oncogenic HPV type does not always provide women with immunity against subsequent infections or reduce the risk of an HPV infection becoming persistent.

Natural exposure to viruses usually results in cell-mediated responses and/or specific antibodies (Arnheim 2005).

• Cell-mediated immune responses involve T-cells (lymphocytes). Cytotoxic T-lymphocytes (CTLs) bind to the surface of infected basal cells that display the antigen and destroy them. A second type of T-lymphocyte, helper T-lymphocytes, recognise infected cells and secrete cytokines, which stimulate inflammation and also attract other immune cells.
  
• Antibody-mediated (or humoral) immunity involves antibodies in body fluids binding to the antigen, marking it out for destruction or destroying it directly.

The oncogenic HPV types are unusual viruses in that the infection is confined to the basal mucosal epithelial cells lining the cervix or genital tract. The infection does not spread to the body in general (ie, there is no viraemia).

The oncogenic HPV types evade the body’s natural immune systems by stimulating epithelial cells to produce cytokines that down-regulate parts of the local immune response, especially the specialist cells that present foreign antigens to the immune system. This reduces the ability of the body to respond to a natural infection, allowing the infection to become established and the oncogenic disease process to begin.

It also means that prior infection with an oncogenic HPV type does not automatically induce immunity against subsequent infection (de Jong et al 2004; Baseman and Koutsky 2005). A woman can be infected with HPV more than once and can experience multiple, persistent infections with oncogenic HPV.

For long-lasting and effective protection against further infections, both humoral and cell-mediated responses often need to be triggered. In particular, B-lymphocytes and T-helper lymphocytes must be sufficiently stimulated to form an immunological memory of the infection, which does not always occur following HPV infection (Gonçalves and Donadi 2004; Viscidi et al 1997). HPV vaccines currently under development would be required to stimulate a humoral and, perhaps, a cell-mediated response, as well as to bypass the down-regulation of the local immune system by stimulating a direct systemic response via intra-muscular injection.

Cell-mediated immunity to HPV

The oncogenic HPVs are unusual viruses in that the infection is confined to the mucosal epithelial cells lining the cervix or genital tract. There is no viraemia.

Following viral infection the virus is able to ‘hijack’ the cell’s normal protein replication apparatus to generate more viral particles. HPVs enter the basal cell nuclei and replicate in low copy numbers separate from the human DNA. The cervical epithelium contains a variety of special cells, which once infected with the HPV, are able to present viral protein fragments (antigens) on the cell surface. Antigen presenting cells (APCs), a class of cells that can include dendritic cells and macrophages, are also recruited; they also display viral antigens on their cell surface, thus helping attract other components of the cell-mediated immune response (Gonçalves and Donadi 2004).

These antigens are recognised by T-lymphocytes. Once stimulated by APCs, helper T-lymphocytes recognise infected cells and secrete cytokines to attract further immune cell types, including CTLs. The CTLs then bind to the surface of infected cells that display the antigen and destroy them. This process is described as the cell-mediated immune response.

In natural infection with oncogenic HPV types it is thought that T-cell-mediated immunity works with the innate immunity to clear HPV in its pre-cancerous forms. However, persistent infection with oncogenic HPV is able to suppress this cell-mediated response.

Antibody-mediated immunity to HPV

Antibody-mediated (or humoral) immunity involves antibodies in body fluids binding to antigens on the surface of infected cells, marking them out for destruction by white blood cells or destroying the infected cell directly.

Humoral immunity is mediated by B-lymphocytes, which differentiate into plasma cells or memory B-cells. The plasma cells provide the initial short-lived, humoral response producing antibodies to combat the presence of specific antigens. Memory B-cells respond to the same antigen at later infections. Once the antigen is detected, the memory B-cells grow and divide to produce an army of antibody-secreting cells to fight the infection. This response is faster, more prolonged and more effective than the primary plasma cell response.

Cross-talk between the humoral immune response and the cell-mediated response is essential for the production of antibodies, and, in particular, helper T-lymphocytes that have been stimulated in response to a HPV infection can then go on to promote this antibody-mediated response (Gonçalves and Donadi 2004).

The IgG antibody is believed to be the main mechanism for preventing infection with oncogenic HPV. The L1 capsid protein of the virus is a key antigen for triggering the production of this antibody. However, most people who come in to contact with oncogenic HPV do not generate enough effective, protective antibodies to block infection. The reason for this is that papillomaviruses are able to evade the immune system by a number of mechanisms. They limit their replication to epithelial rather than basal cells. They disrupt various cytokine signalling pathways. And they also inhibit the expression of viral proteins and their presentation on the cell surface (O'Brien and Saveria Campo 2003). As a consequence, prior infection with an oncogenic HPV type does not automatically induce immunity against subsequent infection, nor does it reduce the risk of future persistent infection with HPV.

To read information on immunology in relation to the cervix click here