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A small proportion of humans show partial or apparently complete innate resistance to HIV, the virus that causes AIDS. The main mechanism is a mutation of the gene encoding
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 p ...
, which acts as a co-receptor for
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 ...
. It is estimated that the proportion of people with some form of resistance to HIV is under 10%.


History

In 1994, Stephen Crohn became the first person discovered to be completely resistant to HIV in all tests performed despite having partners infected by the virus. Crohn's resistance was a result of the absence of a receptor, which prevent the HIV from infecting CD4 present on the exterior of the white blood cells. The absence of such receptors, or rather the shortening of them to the point of being inoperable, is known as the delta 32 mutation. This mutation is linked to groups of people that have been exposed to HIV but remain uninfected such as some offspring of HIV positive mothers, health officials, and sex workers. In early 2000, researchers discovered a small group of sex workers in
Nairobi, Kenya Nairobi ( ) is the capital and largest city of Kenya. The name is derived from the Maasai phrase ''Enkare Nairobi'', which translates to "place of cool waters", a reference to the Nairobi River which flows through the city. The city proper h ...
, who were estimated to have sexual contact with 60 to 70 HIV positive clients a year without signs of infection. These sex workers were not found to have the delta mutation leading scientists to believe other factors could create a genetic resistance to HIV. Researchers from
Public Health Agency of Canada The Public Health Agency of Canada (PHAC; french: Agence de la santé publique du Canada, ASPC) is an agency of the Government of Canada that is responsible for public health, emergency preparedness and response, and infectious and chronic dis ...
have identified 15 proteins unique to those virus-free sex workers. Later, however, some sex workers were discovered to have contracted the virus, leading
Oxford University Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to th ...
researcher Sarah Rowland-Jones to believe continual exposure is a requirement for maintaining immunity.


CCR5 deletion

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
on the surface of white blood cells that is involved in the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...
as it acts as a receptor for
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
s. This is the process by which T cells are attracted to specific tissue and organ targets. Many strains of
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 ...
use CCR5 as a co-receptor to enter and infect host cells. A few individuals carry a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
known as CCR5-Δ32 in the CCR5
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
, protecting them against these strains of HIV. In humans, the ''CCR5'' gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on
chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
. A cohort study, from June 1981 to October 2016, looked into the correlation between the delta 32 deletion and HIV resistance, and found that
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
carriers of the delta 32 mutation are resistant to M-tropic strains of
HIV-1 infection The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabe ...
. Certain populations have inherited the ''Delta 32'' mutation resulting in the
genetic deletion In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...
of a portion of the CCR5 gene.


TNPO3 mutation

In 2019, it was discovered that a mutation of
TNPO3 Transportin-3 is a protein that in humans is encoded by the ''TNPO3'' gene. Function TNPO3 is a nuclear import receptor for serine/arginine-rich (SR) proteins, including Serine/arginine-rich splicing factor 1, which are essential precursor- m ...
that causes type 1F limb-girdle muscular dystrophy (LGMD1F) also causes innate resistance to HIV-1. TNP03 was known to be involved into virus transportation into the infected cells. Blood samples from a family affected by LGMD1F showed a resistance to HIV infection. While the CCR5Δ32 deletion blocks the entry of virus strains that use 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 p ...
receptor, the TNPO3 mutation causing LGMD1F blocks the
CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemokin ...
receptor, making it effective on different HIV-1 strains, due to
HIV tropism HIV tropism refers to the cell type in which the human immunodeficiency virus ( HIV) infects and replicates. HIV tropism of a patient's virus is measured by the Trofile assay. HIV can infect a variety of cells such as CD4+ helper T-cells and m ...
.


Cytotoxic T-lymphocytes

Cytotoxic T-lymphocytes A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...
(CTLs) provide a protective reaction against HIV when consistent exposure to the virus is present. The Nairobi sex workers were found to have these CTLs within genital mucus, preventing the spread of HIV within heterosexual transmission. While creating a protective seal, CTLs become ineffective when lapses in HIV exposure occur, which leads to the possibility of CTLs only being an indicator of other genetic resistances towards HIV, such as
immunoglobulin A Immunoglobulin A (Ig A, also referred to as sIgA in its secretory form) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other typ ...
responses within vaginal fluids.


African nonhuman primates

Chimpanzees in African countries have been found to develop AIDS at a slower rate than humans. This resistance is not due to the primate's ability to control the virus in a manner that is substantially more effective than humans, but rather because of the lack of tissues created within the body that typically progress HIV to AIDS. The chimpanzees also lack CD4 T cells and immune activation that is required for the spread of HIV.


Creating genetic resistance

While
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 multi ...
(ART) has slowed the progression of HIV among patients,
gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
through stem cell research gave resistance to HIV. One method of genetic modification is through the manipulation of
hematopoietic stem cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...
, which replaces HIV genes with engineered particles that attach to chromosomes. Peptides are formed that prevent HIV from fusing to the host cells and therefore stops the infection from spreading. Another method used by the Kiem lab was the release of
zinc finger nuclease Zinc-finger nucleases (ZFNs) are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger domains can be engineered to target specific desired DNA sequences and this enables zin ...
(ZFN), which identifies specific sections of DNA to cause a break in the double helix. These ZFNs were used to target CCR5 in order to delete the protein, halting the course of the infection. Alternatively to gene therapy, medication such as
maraviroc Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class. It was approved for medical use in the Un ...
(MVC) is being used to bind with CCR5 particles, blocking the entry of HIV into the cell. While not effective with all types, MVC has been proven to decrease the spread of HIV through monotherapy as well as combination therapy with ARTs. MVC is the only CCR5 binding drug approved for use by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
, the
European Commission The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body ...
and Health Canada.


HIV resistance as an environmental factor

While the delta mutation has been observed to prevent HIV in specific populations, it has shown little to no effect between healthy individuals and those who are infected with HIV among Iranian populations. This is attributed to individuals being heterozygous for the mutation, which prevents the delta mutation from effectively prohibiting HIV from entering immune cells.


See also

* Discovery and development of CCR5 receptor antagonists *
Entry inhibitor 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 entr ...
*
HIV tropism HIV tropism refers to the cell type in which the human immunodeficiency virus ( HIV) infects and replicates. HIV tropism of a patient's virus is measured by the Trofile assay. HIV can infect a variety of cells such as CD4+ helper T-cells and m ...
*
Timothy Ray Brown Timothy Ray Brown (March 11, 1966September 29, 2020) was an American considered to be the first person cured of HIV/AIDS. Brown was called "The Berlin Patient" at the 2008 Conference on Retroviruses and Opportunistic Infections, where his cure ...
* Stephen Crohn


References


External links


PBS documentary about the discovery of CCR5
{{DEFAULTSORT:Hiv immunity HIV/AIDS Immunology