HIV Disease Progression Rates
Encyclopedia
Following infection with HIV
-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics
and immune function, health care
and co-infections as well as viral genetic variability may affect the rate of progression to AIDS
.
-infected individuals rapidly progress to AIDS
within four years after primary HIV-infection
and are termed Rapid Progressors (RP). Indeed some individuals have been known to progress to AIDS and death within a year after primo-infection. Rapid progression was originally thought to be continent specific, as some studies reported that disease
progression is more rapid in Africa
, but others have contested this view.
that is virally fit and replicates normally, but the infected individual has had a strong and broad set of HIV-specific humoral and cell-mediated response
s that seems to delay the progression to AIDS. In some cohorts, individuals who experience signs of progression, but whose clinical and laboratory parameters remain stable over long periods of time, are classified as Long Term Survivors (LTS).
and in The Gambia
. When these individuals' PBMC
s are stimulated with HIV-1 peptides, they have lymphoproliferative activity and have HIV-1 specific CD8+ CTL activity suggesting that transient infection may have occurred. This does not occur in unexposed individuals. What is interesting, is that the CTL epitope specificity differs between HEPS and HIV positive individuals, and in HEPS, the maintenance of responses appears to be dependent upon persistent exposure to HIV.
and the rapid loss of CD4+ T cell levels versus normal to slow progression to WHO stage 4
and the maintenance of CD4+ T cell counts above 500/µl). The appearance of HIV-1-specific CD8+ cytotoxic T cell
s (CTLs) early after primo-infection has been correlated with the control of HIV-1 viremia. The virus which escapes this CTL response have been found to have mutations in specific CTL epitopes. Individuals with a broad expansion of the V-beta chain of the T cell receptor of CD8+ T cells during primo-infection appear seem to have low levels of virus six to twelve months later, which is predictive of relatively slow disease progression. In contrast, individuals with an expansion of only a single subset of the V-beta chain of the CD8+ T cells are not able to control HIV levels over time, and thus have high levels of virus six to twelve months later. LTNP’s have also been shown to have a vigorous proliferation of circulating activated HIV-1-specific CD4+ T cell and CTL response against multiple epitope
s with no detectable broadly cross-reactive neutralizing antibodies in the setting of an extremely low viral load. However, a few reports have correlated the presence of antibodies against Tat in LTNP status.
than individuals infected with subtype A. In Uganda
, where subtypes A and D are most prevalent, subtype D is associated with faster disease progression compared with subtype A. Age
has also been shown to be a major factor in determining survival and the rate of disease progression, with individuals over 40 years of age at sero-conversion being associated with rapid progression.
and CCR2
) and chemokines (SDF-1). While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV entry; two copies of this gene provide strong protection against HIV infection, although the protection is not absolute. This allele is found in around 10% of European
s but is rare in Africans and Asians. Multiple studies of HIV-infected persons have shown that presence of one copy of this mutation, named CCR5-Δ32 (CCR5 delta 32) delays progression to the condition of AIDS by about 2 years.
The National Institute of Health (NIH) has funded research studies to learn more about this genetic mutation. In such research, NIH has found that there exist genetic tests that can determine if a person has this mutation. Implications of a genetic test may in the future allow clinicians to change treatment for the HIV infection according to the genetic makeup of an individual, Currently there exist several at-home tests for the CCR5 mutation in individuals; however, they are not diagnostic tests.
A relatively new class of drugs for HIV treatment relies on the genetic makeup of the individual. Entry inhibitors
bind to the CCR5 protein to block HIV from binding to the CD4 cell.
by inducing a response and activation of the immune system. This activation facilitates the three key stages of the viral life cycle
: entry to the cell; reverse transcription
and proviral transcription. Chemokine receptor
s are vital for the entry of HIV into cells. The expression of these receptors is inducible by immune activation caused through infection or immunization, thus augmenting the number of cells that are able to be infected by HIV-1. Both reverse transcription of the HIV-1 genome
and the rate of transcription of proviral DNA rely upon the activation state of the cell and are less likely to be successful in quiescent cells. In activated cells there is an increase in the cytoplasm
ic concentrations of mediators required for reverse transcription of the HIV genome. Activated cells also release IFN-alpha which acts on an autocrine and paracrine loop that up-regulates the levels of physiologically active NF-kappa B which activates host cell genes as well as the HIV-1 LTR. The impact of co-infections by micro-organisms such as Mycobacterium tuberculosis
can be important in disease progression, particularly for those who have a high prevalence of chronic
and recurrent acute infections and poor access to medical care. Often, survival depends upon the initial AIDS-defining illness. Co-infection with DNA
virus
es such as HTLV-1, herpes simplex virus-2, varicella zoster virus
and cytomegalovirus
may enhance proviral DNA transcription and thus viral load as they may encode protein
s that are able to trans-activate the expression of the HIV-1 pro-viral DNA. Frequent exposure to helminth infections, which are endemic in Africa
, activates individual immune system
s, thereby shifting the cytokine
balance away from an initial Th1 cell response against viruses and bacteria which would occur in the uninfected person to a less protective T helper 0/2-type response. HIV-1 also promotes a Th1 to Th0 shift and replicates preferentially in Th2 and Th0 cells. This makes the host more susceptible to and less able to cope with infection with HIV-1,viruses and some types of bacteria. Ironically, exposure to dengue virus seems to slow HIV progression rates temporarily.
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
and immune function, health care
Health care
Health care is the diagnosis, treatment, and prevention of disease, illness, injury, and other physical and mental impairments in humans. Health care is delivered by practitioners in medicine, chiropractic, dentistry, nursing, pharmacy, allied health, and other care providers...
and co-infections as well as viral genetic variability may affect the rate of progression to AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
.
Rapid progressors
A small percentage of HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-infected individuals rapidly progress to AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
within four years after primary HIV-infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
and are termed Rapid Progressors (RP). Indeed some individuals have been known to progress to AIDS and death within a year after primo-infection. Rapid progression was originally thought to be continent specific, as some studies reported that disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
progression is more rapid in Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
, but others have contested this view.
Long term non-progressors
Another subset of individuals who are persistently infected with HIV-1, but show no signs of disease progression for over 12 years and remain asymptomatic are classified as Long Term Non-Progressors (LTNP). In these individuals, it seems that HIV-infection has been halted with regard to disease progression over an extended period of time. However, the term LTNP is a misnomer as that progression towards AIDS can occur even after 15 years of stable infection. LTNP are not a homogeneous group regarding both viral load and specific immune responses against HIV-1. Some LTNPs are infected with HIV that inefficiently replicates whilst others are infected with HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
that is virally fit and replicates normally, but the infected individual has had a strong and broad set of HIV-specific humoral and cell-mediated response
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
s that seems to delay the progression to AIDS. In some cohorts, individuals who experience signs of progression, but whose clinical and laboratory parameters remain stable over long periods of time, are classified as Long Term Survivors (LTS).
Highly exposed persistently seronegative
There is another, smaller percentage of individuals who have been recently identified. These are called Highly Exposed Persistently Seronegative (HEPS). This is a small group of individuals and has been observed only in a group of uninfected HIV-negative prostitutes in KenyaKenya
Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...
and in The Gambia
The Gambia
The Republic of The Gambia, commonly referred to as The Gambia, or Gambia , is a country in West Africa. Gambia is the smallest country on mainland Africa, surrounded by Senegal except for a short coastline on the Atlantic Ocean in the west....
. When these individuals' PBMC
PBMC
A peripheral blood mononuclear cell is any blood cell having a round nucleus. For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells , B cells...
s are stimulated with HIV-1 peptides, they have lymphoproliferative activity and have HIV-1 specific CD8+ CTL activity suggesting that transient infection may have occurred. This does not occur in unexposed individuals. What is interesting, is that the CTL epitope specificity differs between HEPS and HIV positive individuals, and in HEPS, the maintenance of responses appears to be dependent upon persistent exposure to HIV.
Prediction of progression rates
During the initial weeks after HIV infection, qualitative differences in the cell-mediated immune response are observed that correlate with different disease progression rates (i.e., rapid progression to WHO stage 4WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents
WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents was first produced in 1990 by the World Health Organization and updated in September 2005...
and the rapid loss of CD4+ T cell levels versus normal to slow progression to WHO stage 4
WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents
WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents was first produced in 1990 by the World Health Organization and updated in September 2005...
and the maintenance of CD4+ T cell counts above 500/µl). The appearance of HIV-1-specific CD8+ cytotoxic T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s (CTLs) early after primo-infection has been correlated with the control of HIV-1 viremia. The virus which escapes this CTL response have been found to have mutations in specific CTL epitopes. Individuals with a broad expansion of the V-beta chain of the T cell receptor of CD8+ T cells during primo-infection appear seem to have low levels of virus six to twelve months later, which is predictive of relatively slow disease progression. In contrast, individuals with an expansion of only a single subset of the V-beta chain of the CD8+ T cells are not able to control HIV levels over time, and thus have high levels of virus six to twelve months later. LTNP’s have also been shown to have a vigorous proliferation of circulating activated HIV-1-specific CD4+ T cell and CTL response against multiple epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
s with no detectable broadly cross-reactive neutralizing antibodies in the setting of an extremely low viral load. However, a few reports have correlated the presence of antibodies against Tat in LTNP status.
HIV subtype variation and effect on progression rates
The HIV-1 subtype that an individual becomes infected with can be a major factor in the rate of progression from sero-conversion to AIDS. Individuals infected with subtypes C, D and G are 8 times more likely to develop AIDSAIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
than individuals infected with subtype A. In Uganda
Uganda
Uganda , officially the Republic of Uganda, is a landlocked country in East Africa. Uganda is also known as the "Pearl of Africa". It is bordered on the east by Kenya, on the north by South Sudan, on the west by the Democratic Republic of the Congo, on the southwest by Rwanda, and on the south by...
, where subtypes A and D are most prevalent, subtype D is associated with faster disease progression compared with subtype A. Age
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
has also been shown to be a major factor in determining survival and the rate of disease progression, with individuals over 40 years of age at sero-conversion being associated with rapid progression.
Host genetic susceptibility
The Centers for Disease Control and Prevention (CDC) has released findings that genes influence susceptibility to HIV infection and progression to AIDS. HIV enters cells through an interaction with both CD4 and a chemokine receptor of the 7 transmembrane family. They first reviewed the role of genes in encoding chemokine receptors (CCR5CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
and CCR2
CCR2
CCR2, short for chemokine receptor 2, is a chemokine receptor.CCR2 has also recently been designated CD192 .-External links:* at...
) and chemokines (SDF-1). While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV entry; two copies of this gene provide strong protection against HIV infection, although the protection is not absolute. This allele is found in around 10% of European
European ethnic groups
The ethnic groups in Europe are the various ethnic groups that reside in the nations of Europe. European ethnology is the field of anthropology focusing on Europe....
s but is rare in Africans and Asians. Multiple studies of HIV-infected persons have shown that presence of one copy of this mutation, named CCR5-Δ32 (CCR5 delta 32) delays progression to the condition of AIDS by about 2 years.
The National Institute of Health (NIH) has funded research studies to learn more about this genetic mutation. In such research, NIH has found that there exist genetic tests that can determine if a person has this mutation. Implications of a genetic test may in the future allow clinicians to change treatment for the HIV infection according to the genetic makeup of an individual, Currently there exist several at-home tests for the CCR5 mutation in individuals; however, they are not diagnostic tests.
A relatively new class of drugs for HIV treatment relies on the genetic makeup of the individual. Entry inhibitors
Entry inhibitors
Entry inhibitors, also known as fusion inhibitors, are a class of antiretroviral drugs, used in combination therapy for the treatment of HIV infection. This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell...
bind to the CCR5 protein to block HIV from binding to the CD4 cell.
The effect of co-infections on progression rates
Coinfections or immunizations may enhance viral replicationDNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
by inducing a response and activation of the immune system. This activation facilitates the three key stages of the viral life cycle
Viral life cycle
Viruses are similar to living organisms, however there are differences. One of the ways a virus can be seen as living is that a virus needs to replicate and create progeny. However, unlike other organisms, a virus cannot survive on its own. It is only active when replicating within a host, using a...
: entry to the cell; reverse transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and proviral transcription. Chemokine receptor
Chemokine receptor
Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. There have been 19 distinct chemokine receptors described in mammals...
s are vital for the entry of HIV into cells. The expression of these receptors is inducible by immune activation caused through infection or immunization, thus augmenting the number of cells that are able to be infected by HIV-1. Both reverse transcription of the HIV-1 genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
and the rate of transcription of proviral DNA rely upon the activation state of the cell and are less likely to be successful in quiescent cells. In activated cells there is an increase in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic concentrations of mediators required for reverse transcription of the HIV genome. Activated cells also release IFN-alpha which acts on an autocrine and paracrine loop that up-regulates the levels of physiologically active NF-kappa B which activates host cell genes as well as the HIV-1 LTR. The impact of co-infections by micro-organisms such as Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
can be important in disease progression, particularly for those who have a high prevalence of chronic
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
and recurrent acute infections and poor access to medical care. Often, survival depends upon the initial AIDS-defining illness. Co-infection with DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es such as HTLV-1, herpes simplex virus-2, varicella zoster virus
Varicella zoster virus
Varicella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and Herpes zoster in adults and rarely in children.-Nomenclature:...
and cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
may enhance proviral DNA transcription and thus viral load as they may encode protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that are able to trans-activate the expression of the HIV-1 pro-viral DNA. Frequent exposure to helminth infections, which are endemic in Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
, activates individual immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
s, thereby shifting the cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
balance away from an initial Th1 cell response against viruses and bacteria which would occur in the uninfected person to a less protective T helper 0/2-type response. HIV-1 also promotes a Th1 to Th0 shift and replicates preferentially in Th2 and Th0 cells. This makes the host more susceptible to and less able to cope with infection with HIV-1,viruses and some types of bacteria. Ironically, exposure to dengue virus seems to slow HIV progression rates temporarily.