Long-term Nonprogressor

Long-term Nonprogressor

Long-term nonprogressors (LTNPs), less commonly called elite controllers, are rare individuals who are infected with HIV, but control the infection without antiretroviral therapy. Many of these patients have been HIV positive for 30 years without progressing to the point of needing to take medication in order not to develop AIDS. They have been the subject of a great deal of research, since an understanding of their ability to control HIV infection may lead to the development of immune therapies or a therapeutic vaccine.

Long-term nonprogressors typically have viral loads under 10,000 copies RNA/ml blood, do not take antiretrovirals, and have CD4+ counts within the normal range. Most people with HIV not on medication have viral loads which are much higher.

It is estimated that around 1 in 500 people with HIV are long-term nonprogressors. Without the symptoms of AIDS, many LTNP patients may not know they are infected. The clinical relevance of the classification "Long-term non-progressor" is not definitive because some patients classified in this category have gone on to develop AIDS. It is likely, however, that these patients were not true LTNP patients.

Genetic traits that confer greater resistance or more robust immune response to HIV are thought to explain why LTNP patients progress to the point of needing to take medication in order not to develop AIDS more slowly than most HIV-infected people. Some LTNP are infected with a weakened or inactive form of HIV, but it is now known that many LTNP patients carry a fully virulent form of the virus. Genetic traits that may affect progression include:

• Gene mutation. A mutation in the FUT2 gene affects the progression of HIV-1 infection. 20% of Europeans who have that mutation are called "non secretor" because of their absence of a certain type of antigen that provide also a strong resistance against norovirus

• Mitochondrial DNA. Different types of Mitochondrial DNA in humans gives an increased or a decreased rate of HIV progression.

• Receptor mutations. A low percentage of long-term nonprogressors have been shown to have inherited mutations of the CCR5 receptor of T cell lymphocytes. HIV uses CCR5 to enter these cells. It is believed that the Δ32 (delta 32) variant of CCR5 impairs HIV ability to infect cells and cause disease. An understanding of this mechanism led to the development of a class of HIV medicines, the entry inhibitors. The presence of this mutation, however, is not a unifying theme among LTNPs and is observed in a exceedingly small number of these patients.

• HLA type has also been correlated with long-term non-progressor cohorts. In particular, a high percentage of people possessing HLA-B*5705 and/or HLA-B*2705 are more likely to exhibit control over HIV (Migueles et al., 2000).

• Antibody production. All individuals with HIV make antibodies against the virus. In most patients, broadly neutralizing antibodies do not emerge until ~4 years after the initial infection. At this point, the latent reservoir has already been established and the presence of broadly neutralizing antibodies is not enough to prevent disease progression. In some rare patients, these antibodies emerge earlier and can result in a delayed disease course. These patients, however, are not typically classified as LTNPs, but rather as slow progressors, who will eventually develop AIDS. Induction of broadly neutralizing antibodies in healthy individuals is a potential strategy for a preventive HIV vaccine.