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 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.^[1]

Long-term nonprogressors have viral loads under 50, do not take antiretrovirals, and have CD4+ counts within the normal range .^[2] 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.^[3] Without the symptoms of AIDS, many LTNP may not know they are infected.^[4] 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 LTNPs.

Genetic traits that confer greater resistance or more robust immune response to HIV are thought to explain why LTNP progress to AIDS more slowly than most HIV-infected people.^[5][6] Some LTNP are infected with a weakened or inactive form of HIV, but it is now known that many LTNPs carry a fully virulent form of the virus. Genetic traits that may affect progression include:

• 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.^[7] 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.

Long-term progressors, naturally-occurring genetic mutation, and anti-HIV gene therapy

According to a Monday, September 19, 2011 Reuters U.S. edition online news story by Deena Beasley:

"An early stage trial of Sangamo Biosciences Inc.'s HIV treatment found that the gene therapy reduced levels of the virus and even eliminated it in one patient with a naturally occurring gene mutation.

The very small Phase I trial tested the SB-728-T gene therapy, which is designed to disrupt the CCR5 gene used by HIV to infect cells of the immune system.

If shown to be safe and effective, the treatment could end the need for the antiretroviral drugs now used to keep the virus that causes AIDS in check by suppressing viral replication in the blood.

Trial results presented in Chicago on Sunday at the Interscience Conference on Antimicrobial Agents and Chemotherapy show a "statistically significant relationship between estimated modification of both copies of the CCR5 gene and viral load," said Dr. Carl June, trial investigator and director of translational research at the University of Pennsylvania's cancer research institute.

In a statement, June said the results suggest the need to increase the frequency of the modified cells in HIV-infected patients, which could lead to a "functional cure" for AIDS, but the means of achieving this have not been clarified.

Sangamo said earlier this year that a single infusion of the treatment improved immune system damage in nearly all of the subjects analyzed in the first trial of the therapy in humans.

The 10 patients in the trial were on antiretroviral therapy when the study began. After four weeks, six of them went on a "treatment interruption," during which they stopped taking antiviral medication for 12 weeks.

Viral load decreased in three of the six subjects, with one patient's viral load reduced to undetectable levels. That patient carried a naturally occurring mutation in one copy of his CCR5 gene.

Humans contain two copies of each gene, one from the father and one from the mother, which sometimes are referred to as the alleles of a gene.

"Since one copy of his gene was already disrupted naturally, twice as many of his cells were 'biallelically' modified," Sangamo Chief Executive Officer Edward Lanphier said in a telephone interview, meaning that both members of the CCR5 gene pair were knocked out.

He estimated that between 5 percent and 10 percent of HIV patients carry the genetic mutation.

Around 33 million people worldwide have the human immunodeficiency virus (HIV) that causes AIDS.

Lanphier said Sangamo will move ahead with a strategy to maximize the number of cells that can be "biallelically" modified by SB-728-T. Options include targeting only the small segment of patients with mutated CCR5 genes or using "strategies that boost the amount of engraftment of modified cells.""^[8]

References

External links

• The International HIV Controllers Study
• The Zephyr Foundation