Introduction to HIV types, groups and subtypes

Introduction to HIV types, groups and subtypes

HIV is a highly variable virus which mutates very readily. This means there are many different strains of HIV, even within the body of a single infected person.
Based on genetic similarities, the numerous virus strains may be classified into types, groups and subtypes.
There are two types of HIV: HIV-1 and HIV-2. Both types are transmitted by sexual contact, through blood, and from mother to child, and they appear to cause clinically indistinguishable AIDS. However, it seems that HIV-2 is less easily transmitted, and the period between initial infection and illness is longer in the case of HIV-2.
Worldwide, the predominant virus is HIV-1, and generally when people refer to HIV without specifying the type of virus they will be referring to HIV-1. The relatively uncommon HIV-2 type is concentrated in West Africa and is rarely found elsewhere.
Subtypes of HIV-1
The strains of HIV-1 can be classified into three groups : the "major" group M, the "outlier" group O and the "new" group N. These three groups may represent three separate introductions of simian immunodeficiency virus into humans.
Group O appears to be restricted to west-central Africa and group N - discovered in 1998 in Cameroon - is extremely rare. More than 90% of HIV-1 infections belong to HIV-1 group M and, unless specified, the rest of this page will relate to HIV-1 group M only.
Within group M there are known to be at least nine genetically distinct subtypes (or clades) of HIV-1. These are subtypes A, B, C, D, F, G, H, J and K.
Occasionally, two viruses of different subtypes can meet in the cell of an infected person and mix together their genetic material to create a new hybrid virus (a process similar to sexual reproduction, and sometimes called "viral sex").1 Many of these new strains do not survive for long, but those that infect more than one person are known as "circulating recombinant forms" or CRFs. For example, the CRF A/B is a mixture of subtypes A and B.
The classification of HIV strains into subtypes and CRFs is a complex issue and the definitions are subject to change as new discoveries are made. Some scientists talk about subtypes A1, A2, A3, F1 and F2 instead of A and F, though others regard the former as sub-subtypes.
Subtypes E and I? : One of the CRFs is called A/E because it is thought to have resulted from hybridization between subtype A and some other "parent" subtype E. However, no one has ever found a pure form of subtype E. Confusingly, many people still refer to the CRF A/E as "subtype E" (in fact it is most correctly called CRF01_AE).2
A virus isolated in Cyprus was originally placed in a new subtype I, before being reclassified as a recombinant form A/G/I. It is now thought that this virus represents an even more complex CRF comprised of subtypes A, G, H, K and unclassified regions. The designation "I" is no longer used.
Different subtypes and CRFs
The HIV-1 subtypes and CRFs are very unevenly distributed throughout the world, with the most widespread being subtypes A and C.
Subtype A and CRF A/G predominate in West and Central Africa, with subtype A possibly also causing much of the Russian epidemic.4
Historically, subtype B has been the most common subtype/CRF in Europe, the Americas, Japan and Australia. Although this remains the case, other subtypes are becoming more frequent and now account for at least 25% of new infections in Europe.
Subtype C is predominant in Southern and East Africa, India and Nepal. It has caused the world's worst HIV epidemics and is responsible for around half of all infections.
Subtype D is generally limited to East and Central Africa. CRF A/E is prevalent in South-East Asia, but originated in Central Africa. Subtype F has been found in Central Africa, South America and Eastern Europe. Subtype G and CRF A/G have been observed in West and East Africa and Central Europe.
Subtype H has only been found in Central Africa; J only in Central America; and K only in the Democratic Republic of Congo and Cameroon.
A study presented in 2006 found that Ugandans infected with subtype D or recombinant strains incorporating subtype D developed AIDS sooner than those infected with subtype A, and also died sooner. The study's authors suggested that subtype D is more virulent because it is more effective at binding to immune cells.5 This result was supported by another study presented in 2007, which found that Kenyan women infected with subtype D had more than twice the risk of death over six years compared with those infected with subtype A.6 An earlier study of sex workers in Senegal, published in 1999, found that women infected with subtype C, D or G were more likely to develop AIDS within five years of infection than those infected with subtype A.
Differences in transmission
It has been observed that certain subtypes/CRFs are predominantly associated with specific modes of transmission. In particular, subtype B is spread mostly by homosexual contact and intravenous drug use (essentially via blood), while subtype C and CRF A/E tend to fuel heterosexual epidemics (via a mucosal route).
Whether there are biological causes for the observed differences in transmission routes remains the subject of debate. Some scientists, such as Dr Max Essex of Harvard, believe such causes do exist. Among their claims are that subtype C and CRF A/E are transmitted much more efficiently during heterosexual sex than subtype B.8 9 However, this theory has not been conclusively proven.
More recent studies have looked for variation between subtypes in rates of mother-to-child transmission. One of these found that such transmission is more common with subtype D than subtype A.12 Another reached the opposite conclusion (A worse than D), and also found that subtype C was more often transmitted that subtype D. A third study concluded that subtype C is more transmissible than either D or A. Other researchers have found no association between subtype and rates of mother-to-child transmission.
Until about 1994, it was generally thought that individuals do not become infected with multiple distinct HIV-1 strains. Since then, many cases of people coinfected with two or more strains have been documented.
All cases of coinfection were once assumed to be the result of people being exposed to the different strains more or less simultaneously, before their immune systems had had a chance to react. However, it is now thought that "superinfection" is also occurring. In these cases, the second infection occurred several months after the first. It would appear that the body's immune response to the first virus is sometimes not enough to prevent infection with a second strain, especially with a virus belonging to a different subtype. It is not yet known how commonly superinfection occurs, or whether it can take place only in special circumstances.
Tests for HIV
Initial tests for HIV are usually conducted using the EIA (or ELISA) antibody test or a rapid antibody test.
EIA tests which can detect either one or both types of HIV have been available for a number of years. According to the US Centers for Disease Control and Prevention, current HIV-1 EIAs "can accurately identify infections with nearly all non-B subtypes and many infections with group O HIV subtypes."21 However, because HIV-2 and group O infections are extremely rare in most countries, routine screening programs might not be designed to test for them. Anyone who believes they may have contracted HIV-2, HIV-1 group O or one of the rarer subtypes of group M should seek expert advice.
Rapid tests - which can produce a result in less than an hour - are becoming increasingly popular. Most modern rapid HIV-1 tests are capable of detecting all the major subtypes of group M.22 Rapid tests which can detect HIV-2 are also now available.
Treatment implications
Most current HIV-1 antiretroviral drug regimens were designed for use against subtype B, and so hypothetically might not be equally effective in Africa or Asia where other strains are more common. At present, there is no compelling evidence that subtypes differ in their sensitivity to antiretroviral drugs. However, some subtypes may occasionally be more likely to develop resistance to certain drugs. In some situations, the types of mutations associated with resistance may vary. This is an important subject for future research.
The effectiveness of HIV-1 treatment is monitored using viral load tests. It has been demonstrated that some such tests are sensitive only to subtype B and can produce a significant underestimate of viral load if used to process other strains. The latest tests do claim to produce accurate results for most Group M subtypes, though not necessarily for Group O. It is important that health workers and patients are aware of the subtype/CRF they are testing for and of the limitations of the test they are applying.
Not all of the drugs used to treat HIV-1 infection are as effective against HIV-2. In particular, HIV-2 has a natural resistance to NNRTI antiretroviral drugs and they are therefore not recommended. As yet there is no FDA-licensed viral load test for HIV-2 and those designed for HIV-1 are not reliable for monitoring the other type. Instead, response to treatment may be monitored by following CD4+ T-cell counts and indicators of immune system deterioration. More research and clinical experience is needed to determine the most effective treatment for HIV-2
The development of an AIDS vaccine is affected by the range of virus subtypes as well as by the wide variety of human populations who need protection and who differ, for example, in their genetic make-up and their routes of exposure to HIV. In particular, the occurrence of superinfection indicates that an immune response triggered by a vaccine to prevent infection by one strain of HIV may not protect against all other strains. The effectiveness of a vaccine is likely to vary in different populations unless some innovative method is developed which guards against many virus strains.
Inevitably, different types of candidate vaccines will have to be tested against various viral strains in multiple vaccine trials, conducted in both high-income and developing countries.
Types of HIV Infections (AIDS)
For the first few years of the AIDS epidemic, it appeared that some HIV-infected people sickened and died quickly while the others stayed healthy indefinitely or slowly progressed into sickness. Now it appears the greater majority of HIV-infected will gradually become very sick and eventually die. There are reports of long-term survivors of HIV infection; but, they seem to be the exception rather than the rule.
The average (the mean) incubation time for HIV infection is 10 years. Incubation time means the time from initial infection until the development of "full-blown AIDS," discussed below. The average is a bell curve, with 10 years at the center. Some individuals develop illness sooner than 10 years and some later than 10 years.
Most symptoms and diseases common to HIV infection are listed in Figures 4, 5 and 6. The presence of these symptoms and diseases varies from one patient to another. These diseases may occur in sequence or simultaneously.
Obviously, many of these symptoms can be caused by a number of common illnesses. These diseases are listed here for the sake of education, not for the purpose of self-diagnosis. In case of any persistent illness, consult your health care provider.
The popular classification system of HIV infections, used here, is a collection of haphazard definitions that evolved as the AIDS epidemic unfolded. These labels are ones of convenience, not ones of scientific or medical accuracy. Medical authorities use different, more complex, classification systems.
Basically, four loosely defined different stages of HIV infection exist: I ) the healthy carrier state, 2) the lymphadenopathy syndrome (LAS), 3) AIDS-related complex (ARC), and 4) AIDS or "frank AIDS," or "full-blown AIDS." These forms or the symptoms of each may overlap the other.
Healthy Carrier State
A carrier is someone who is infected with a disease and shows no clinical symptoms, but who is capable of infecting other people with the disease. ("Clinical" means "seen in the doctors office.")
HIV has been isolated (removed) and cultured ("grown" in a laboratory dish) from healthy people who show no clinical signs of HIV infection.
It is not yet clear when an HIV-infected person becomes infectious. At this time, the only safe practice is to assume that anyone carrying the virus is capable of transmitting it to others.
Lymphadenopathy Syndrome (LAS)
Lymphadenopathy Syndrome (LAS) is a mild form of HIV infection, generally characterized by some of the symptoms in Figure 4.
Lymphadenopathy means "disease of the lymphatic system." The lymphatic system is the human body's second fluid system which contains a clear fluid called lymph (see Figure 3). The lymphatic system aids the blood system by draining fluid out of the body' s tissues. The lymphatic system is not a closed loop like the bloodstream, meaning it does not flow in a circle, and it has no pump like the heart. Nevertheless, lymph flows from smaller vessels into larger lymph ducts in the upper chest. In doing so, lymphatic fluid passes through a series of filtering stations called lymph nodes, or lymph glands. Lymph nodes filter bacteria (one-celled organisms), foreign substances, and dead white blood cells out of the fluid.
The lymphatic system is a vital part of the body's immune system. Lymph nodes store and mature lymphocytes and other white blood cells and also manufacture antibodies. T-cells and macrophages can migrate back and forth between the blood system and the lymphatic system, perhaps exposing newly generating cells to HIV during their formative stages.
One of the key signs of lymphadenopathy is swollen lymph glands. Of course, any infection, such as the flu, causes the lymph nodes to swell; but, nodal swelling due to normal infections passes quickly. With HIV infection, this nodal swelling may persist for months, with no other signs of a temporary infectious disease. Consequently, lymphadenopathy is sometimes called persistent generalized lymphadenopathy (PGL).

Symptoms of Lymphadenopathy Syndrome (LAS)
• Unexplained fever
• Difficulty in swallowing
• Swollen glands
• Fatigue/Lethargy
• Night sweats and chills
• Apathy
• Gradual loss of weight
• Diarrhea
• Sore throat
• Impotence
AIDS-related Complex (ARC)
AIDS-related Complex is a more advanced level of HIV infection. Symptoms generally include the symptoms of lymphadenopathy, plus abnormal body conditions revealed by laboratory tests, and/or the presence of one or more opportunistic infections.
A person with ARC has a discomforting illness. His or her everyday activity may be restricted and he or she is probably manifesting bouts of illness that require short-term or long-term medical treatment in and out of the hospital.
Acquired Immune Deficiency Syndrome (AIDS)
AIDS is the "full-blown" syndrome, also called "frank" AIDS. Patients suffering from AIDS often have any number of the opportunistic diseases listed in Figure 6. These diseases develop because of the widespread failure of the immune system. Drug treatments are available for many of these infections; but, without the support of the immune system, the drugs fail to cure the disease fully or are unable to keep the disease from returning. These opportunistic infections, curable under other circumstances, cause the death of most AIDS patients.
Symptoms and Conditions of ARC and AIDS
• Anergy: lack of skin allergic response
• Anemia: lack of red blood cells
• Autoimmune Disorders: immune system attacks own body
• Candidiasis/Oral Thrush: See Figure 6
• Hyperplasia: excessive growth of normal cells in organ
• Kidney Dysfunction: kidneys fail or function poorly
• Leukopenia: decreased number of leukocytes (white blood cells that engulf germs)
• Lymphomas: lymphatic system cancers
• Lymphopenia: decreased number of lymphocytes
• Nerve Damage: possible blindness, deafness, paralysis
• Oral Thrush: caused by Epstein-Barr Virus (Figure 6)
• Wasting: severe weight loss, perhaps death, from diarrhea and malnutrition
Diseases Common to AIDS
Pneumocystis carinii pneumonia (PCP).
Caused by fungus-like single-celled parasite, Pneumocystis carinii, common world-wide. Infects lungs. Previous to AIDS, found in kidney transplant patients whose immune system had been chemically suppressed. Occurs in 60% to 80% of AIDS patients. Initially responsible for 30% to 50% of deaths among AIDS patients, now brought under better control due to chemical prophylaxis, that is, chemically treating the patient before symptoms occur.
Kaposi's sarcoma (KS).
Malignant skin cancer. Appear first as pink, purple or brown lesions (wounds), usually on arms and/or legs; then spreading around body. In AIDS patients, may spread to gastrointestinal tract, lungs, other internal organs. Initially occurred in 46% of homosexual AIDS patients, in only 3.8% of heterosexual IV drug abuser AIDS patients. Onset is statistically associated, in homosexual males, with oral-anal sex and fecal (feces) contact-possible infectious agent involved.
Toxoplasmosis.
Caused by Toxoplasmosa gondii. Infects blood and many tissues. Common to humans, many domestic and wild animals. Humans may catch from droppings of cats and undercooked meat, especially mutton. In AIDS patients, tendency to infect tissues of central nervous system (brain and nerves). Also causes pneumonia and hepatitis inflammation/dysfunction of the liver). Many minor, non-life-threatening outbreaks occur in day-care centers. In AIDS patients, can be a major cause of mortality.


Candidiasis.
Caused by species of Candida, a fungus common to skin, mouth, vagina, gastrointestinal tract of humans. In AIDS patients, usually takes oral form: white spots or patches on lateral sides of tongue, perhaps inside mouth on mucous membranes of cheeks; commonly lodges under nailbeds and skin around armpits, groin, and rectum. Sometimes affects lungs. Frequently, first clinical (as seen in doctor's office) sign of HIV infection .
Cryptococcosis.
Caused by Cryptococcus neoformans, a fungus found in pigeon manure. Common among humans and other mammals, especially cats. Causes pneumonia in rare instances, most often causes meningitis (inflammation of the spinal cord and brain membranes). Also causes endocarditis (inflammation of lining of heart); and skin ulcers. Some increasing success with drug therapy.
Herpes infections.
Caused by herpes simplex viruses 1 (cold sores on lips) and 2 (sores on genitals). In HIV-infected patients, herpes simplex infections form chronic ulcers, often affecting face and sometimes the eyes; anal area often affected in homosexual males. Herpes infections are commonly found in people who are not infected with HIV; forming a cluster(s) of small, painful blisters, often, but not necessarily, on face.
Herpes zoster infection.
Caused by another herpes virus. Also known as shingles or chickenpox. Herpes zoster viruses may remain latent (inactive) for years (perhaps left over from childhood), but may be reactivated by HIV infection, causing inflammation of the spinal and cranial ganglia (nerve roots). In AIDS patients, can be disseminated (widespread) throughout the body. Often an initial clinical symptom in HIV-infected individuals. Herpes zoster is common among people not infected with HIV.
Mycobacterium infection.
Caused by Mycobacterium avium intracellulare, a bacterium commonly found in human saliva. Causes type of tuberculosis in humans, producing lesions in lungs. Disseminated, it cause problems in the intestines, blood, liver, and spleen.
Epstein-Barr infection.
Caused by Epstein-Barr virus (EBV), suspected cause of mononucleosis and some lymphomas (cancers of the lymph tissue). Implicated in number of auto-immune conditions (body's immune system attacking itself, as sometimes occurs in advanced HIV infection.) Thought to disrupt T-cell function. In HIV-infected, causes oral hairy leukoplakia, fuzzy white spots on the tongue which do not rub off as does "hairy tongue" caused by smoking. Possibly remains dormant until HIV infection occurs.
Cytomegalovirus (CMV) infection.
Normally present in salivary glands of humans. Often widely scattered throughout the body in patients with advanced HIV infection. Causes problems in eyes, colon, lungs, liver, and adrenal glands. Suspected in promoting appearance of Kaposi's sarcoma. After PCP prophylaxis became effective, CMV infection became the major cause of mortality among AIDS patients. Cytomegalovirus is frequently spread in day-care centers, where it has been shown to survive on toys and plexiglass for 30 minutes.
Cryptosporidiosis.
An enteritis (inflammation/swelling of intestines) caused by Cryptosporidia muris and/or C. difficile; a one-celled parasite common to domestic and wild animals. Many minor, non-life-threatening outbreaks occur in day-care centers. In AIDS patients, may be major cause of mortality.
Tuberculosis (TB).
Caused by Mycobacterium tuberculosis, a bacterium and a non-opportunistic infection found in non-HIV-infected people. Infects lungs, disseminated in some AIDS patients. A major killer in the past, social hygiene education and effective medical treatment eliminated TB from most of the Western world, except among populations lacking adequate access to medical care. Statistically associated with AIDS (found in some AIDS patients), it may reflect socio-economic status rather than being an opportunistic infection due to AIDS. Infection may occur prior to HIV infection as a damaged immune system is not required to catch TB.