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Long-term nonprogressors (LTNPs), sometimes also called elite controllers, are individuals infected with
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
, who maintain a
CD4 In molecular biology, CD4 ( cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendriti ...
count greater than 500 without
antiretroviral therapy The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple ...
with a detectable viral load. 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. The classification "Long-term non-progressor" is not permanent, because some patients in this category have gone on to develop AIDS. Long-term nonprogressors typically have viral loads under 10,000 copies /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.
Genetic trait Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wo ...
s that confer greater resistance or more robust immune response to HIV are thought to explain why LTNP patients are able to live much longer with HIV than patients who are not LTNP. 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 Galactoside 2-alpha-L-fucosyltransferase 2 is an enzyme that in humans is encoded by the ''FUT2'' gene. It affects the secretor status of ABO antigens. Approximately 20% of Caucasians are non-secretors due to the G428A (rs601338) and C571T (rs49 ...
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 also provides strong resistance against
norovirus Norovirus, sometimes referred to as the winter vomiting disease, is the most common cause of gastroenteritis. Infection is characterized by non-bloody diarrhea, vomiting, and stomach pain. Fever or headaches may also occur. Symptoms usually deve ...
. * Mitochondrial DNA: Different
mitochondrial DNA Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DN ...
haplotype A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA org ...
s in humans may increase or decrease rates of AIDS progression. Haplotypes associated with more loosely coupled mitochondrial respiration, with reduced ATP and ROS generation, have been associated with faster progression and vice versa. * Receptor mutations: A low percentage of long-term nonprogressors have been shown to have inherited mutations of the
CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 pr ...
receptor of
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
s. 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 Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D. HIV entry ...
. The presence of this mutation, however, is not a unifying theme among LTNPs and is observed in an exceedingly small number of these patients. *
HLA type The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
has also been correlated with long-term non-progressor cohorts. In particular, strong correlations have been found between possessing the class 1 HLA-B*5701, HLA-B*5703, and/or HLA-B*2705 alleles and ability to exert control over HIV. * Antibody production: All individuals with HIV make
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
against the virus. In most patients, broadly neutralizing antibodies do not emerge until approximately 2–4 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, as is the elicitation of these antibodies through rationally designed immunogens. Direct production of these antibodies in somatic tissue through plasmid transfection also poses a viable method for making these antibodies endogenously. *
APOBEC3G APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic subunit 3G) is a human enzyme encoded by the ''APOBEC3G'' gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in ...
protein production: In a small number of people infected with HIV, the virus is naturally suppressed without medical treatment. These people may carry high quantities of a protein called
APOBEC3G APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic subunit 3G) is a human enzyme encoded by the ''APOBEC3G'' gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in ...
that disrupts viral replication in cells. APOBEC3G, or "A3" for short, is a protein that sabotages reverse transcription, the process HIV relies on for its replication. This process involves the virus transcribing its single-stranded RNA genome into double-stranded DNA that is incorporated into the cell's genome. A3 usually stops dormant viruses in the human genome, called
endogenous retrovirus Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome (lo ...
es, from reawakening and causing infections. The 'long-term nonprogressors' term is used for HIV carriers only but the wide term
asymptomatic carrier An asymptomatic carrier is a person or other organism that has become infected with a pathogen, but shows no signs or symptoms. Although unaffected by the pathogen, carriers can transmit it to others or develop symptoms in later stages of the ...
is well known for many other infections.


Clearance of the virus

Recently, there have been reports of elite controllers who maintain undetectable viral loads. In 2019, an American named Loreen Willenberg was announced as the first such case. In 2021, an Argentinian dubbed "the Esperanza patient" after the town in which she lives was also identified. Willemberg had received antiretroviral therapy but stopped treatment at some point. The Argentinian patient took antiretroviral therapy only while pregnant, but her viral viral was nevertheless reported to be undetectable years after treatment discontinuation. This could inform the development of a "sterilising cure."


See also

* Innate resistance to HIV *
HIV/AIDS research HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV. Transmission A body of sci ...
* Stephen Crohn * Timothy Ray Brown (The Berlin patient) * Adam Castillejo (the London patient) *
HIV-positive people HIV-positive people, seropositive people or people who live with HIV are people who have the human immunodeficiency virus HIV, the agent of the currently incurable disease AIDS. According to estimates by WHO and UNAIDS, 34.2 million people were i ...


References

*


External links


The International HIV Controllers Study

The Zephyr Foundation
{{DEFAULTSORT:Long-Term Nonprogressors HIV/AIDS HIV/AIDS research