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HIV Strains: Types, Groups and Subtypes

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.

What is the difference between HIV-1 and HIV-2?


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.

How many subtypes of HIV-1 are there?


The strains of HIV-1 can be classified into four groups: the "major" group M, the "outlier" group O and two new groups, N
and P. These four groups may represent four separate introductions of simian immunodeficiency virus into humans.

HIV types, groups and subtypes

Group O appears to be restricted to west-central Africa and group N - a strain discovered in 1998 in Cameroon - is
extremely rare. In 2009 a new strain closely relating to gorilla simian immunodeficiency virus was discovered in a
Cameroonian woman. It was designated HIV-1 group P. 1 More than 90 percent 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. 2
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"). 3 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.

What about 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). 4
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. 5

Where are the different subtypes and CRFs found?


The HIV-1 subtypes and CRFs are typically associated with certain geographical regions, with the most widespread being
subtypes A and C. As studies have shown, individuals are increasingly presenting with sub-types not native to the country
of diagnosis. 6 7 For example, a rise of non-B sub-types among men who have sex with men (MSM) in the UK has been
identified. 8

Subtype A and CRF A/G predominate in West and Central Africa, with subtype A possibly also causing much of
the Russian epidemic. 9

Historically, subtype B has been the most common subtype/CRF in Europe, the Americas, Japan and Australia
and is the predominant sub-type found among MSM infected in Europe. 10 Although this remains the case, other
subtypes are becoming more frequent and now account for at least 25 percent of new HIV 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.

As a Belgium study highlighted, local epidemics can be better understood if sub-types, patient demographics and
transmission routes are recorded. 11 Furthermore, the availability of this data can be used to target risk groups more
accurately and to improve the effectiveness of prevention strategies.

Are more subtypes likely to "appear"?


It is almost certain that new HIV genetic subtypes and CRFs will be discovered in the future, and indeed that new ones will
develop as virus recombination and mutation continue to occur. The current subtypes and CRFs will also continue to
spread to new areas as the global epidemic continues.

The implications of variability


Does subtype affect disease progression?
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, if they did not receive antiretroviral
treatment. The study's authors suggested that subtype D is more virulent because it is more effective at binding to immune
cells. 12 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. 13 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. 14
Several studies conducted in Thailand suggest that people infected with CRF A/E progress faster to AIDS and death than
those infected with subtype B, if they do not receive antiretroviral treatment. 15

Are there differences in transmission?


It has been observed that certain subtypes/CRFs are predominantly associated with specific modes of transmission. 16 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. 17 18 However, this theory
has not been conclusively proven. 19 20
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. 21 Another reached the opposite
conclusion (A worse than D), and also found that subtype C was more often transmitted that subtype D. 22 A third study
concluded that subtype C is more transmissible than either D or A. 23 Other researchers have found no association
between subtype and rates of mother-to-child transmission. 24 25 26 27

Is it possible to be infected more than once?


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. 28 29 30 31

Do HIV antibody tests detect all types, groups and subtypes?


Initial tests for HIV are usually conducted using the EIA (or ELISA) antibody test or a rapid antibody test. 32
Compared with first generation EIA antibody tests that were initially developed, third and fourth generation EIA antibody
tests are significantly more accurate. Unlike previous tests, the fourth generation test detects HIV antibodies and antigens
simultaneously. 33 The WHO recommends that tests should have an accuracy rate of 99 percent and whilst most do, this
may vary slightly between the test brands. 34 35 36
The most-up-to date (fourth generation) EIA tests detect both HIV-1 and HIV-2 infections. 37 Although most HIV infections
are HIV-1 group M, EIA tests are also able to detect infections with rare groups and subtypes.
However, as HIV-2 and group O infections are extremely rare in most countries, routine screening programs might not be
designed to test for them. 38 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.

What are the treatment implications?

An HIV positive man sitting at home before taking his antiretroviral drugs

Although most current HIV-1 antiretroviral drugs were designed for use against subtype B, there is no compelling evidence
that they are any less effective against other subtypes. Nevertheless, some subtypes may be more likely to develop
resistance to certain drugs, and the types of mutations associated with resistance may vary. 39 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 viral load
tests are sensitive only to subtype B and can produce a significant underestimate of viral load if used to process other
strains. 40 41 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. 42 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. 43 More
research and clinical experience is needed to determine the most effective treatment for HIV-2.

What are the implications for an AIDS vaccine?


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 increasing variety of sub-types found within

countries suggests that the effectiveness of a vaccine is likely to vary between populations, unless an innovative method is
developed which guards against many virus strains. 44
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.

References
expand >

Sources
UNAIDS Questions and Answers II, Section I, July 2004.
- See more at: http://www.avert.org/hiv-types.htm#sthash.5b7aZvdn.dpuf

Subtypes of HIV

Human
immunodeficiency virus

Phylogenetic Tree of the SIV


and HIV viruses.

Virus classification
Group:

Group
VI

(ssRN

A-RT)

Family:

Retrovi
ridae

Genus:

Lentivi
rus
Species

Human
immunodeficiency
virus 1

Human
immunodeficiency
virus 2

International
Statistical
Classification of
Diseases and Related
Health Problems
Codes
Classification and external
resources

ICD-10

B2
0B2
4

ICD-9-CM

04
204

One of the obstacles to treatment of the human immunodeficiency virus is its high genetic variability.[1] HIV can be
divided into 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
endangered west African primate sooty mangabey.[2] HIV-1 viruses may be further divided into groups. The HIV-1
group M viruses predominate and are responsible for the AIDS pandemic. Group M can be further subdivided into
subtypes based on genetic sequence data. Some of the subtypes are known to be more virulent or are resistant to
different medications. Likewise, HIV-2 viruses are thought to be less virulent and transmissible than HIV-1 M group
viruses, although HIV-2 is known to cause AIDS.

Major types
HIV-1[
HIV-1 is the most common and pathogenic strain of the virus. Scientists divide HIV-1 into a major group (Group M)
and two or more minor groups. Each group is believed to represent an independent transmission of SIV into
humans (but subtypes within a group are not).[2] A total of 39 ORFs are found in all six possible reading frames (RFs)
of HIV-1 complete genome sequence,[3] but only a few of them are functional.
Group M[]
With 'M' for "major", this is by far the most common type of HIV, with more than 90% of HIV/AIDS cases deriving
from infection with HIV-1 group M. The M group is subdivided further into clades, called subtypes, that are also
given a letter. There are also "circulating recombinant forms" or CRFs derived from recombination between viruses
of different subtypes which are each given a number. CRF12_BF, for example, is a recombination between subtypes
B and F.

Subtype A is common in West Africa.[4]

Subtype B is the dominant form in Europe, the Americas, Japan, Thailand, and Australia. [5]

Subtype C is the dominant form in Southern Africa, Eastern Africa, India, Nepal, and parts of China. [5]

Subtype D is generally only seen in Eastern and central Africa. [5]

(Subtype E) has never been identified as a nonrecombinant, only recombined with subtype A as CRF01_AE.
[5]

Subtype F has been found in central Africa, South America and Eastern Europe. [6]

Subtype G (and the CRF02_AG) have been found in Africa and central Europe. [6]

Subtype H is limited to central Africa.[6]

(Subtype I) was originally used to describe a strain that is now accounted for as CRF04_cpx, with the cpx for
a "complex" recombination of several subtypes.[citation needed]
Subtype J is primarily found in North, Central and West Africa, and the Caribbean [7]

Subtype K is limited to the Democratic Republic of Congo and Cameroon.[6]

These subtypes are sometimes further split into sub-subtypes such as A1 and A2 or F1 and F2. [citation needed] In 2015, the
strain CRF19, a recombinant of subtype A, subtype D and subtype G, with a subtype D protease, was found to be
strongly associated with rapid progression to AIDS in Cuba.[8] This is not thought to be a complete or final list, and
further types are likely to be found.[9]

HIV-1 subtype prevalence in 2002

Group N[edit]
The 'N' stands for "non-M, non-O". This group was discovered in 1998 and has only been seen in Cameroon. As of
2006, only 10 Group N infections had been identified. [10]
Group O
The O ("Outlier") group is not usually seen outside of West-central Africa. It is reportedly most common in
Cameroon, where a 1997 survey found that about 2% of HIV-positive samples were from Group O. [11] The group
caused some concern because it could not be detected by early versions of the HIV-1 test kits. More advanced HIV
tests have now been developed to detect both Group O and Group N.[12]
Group P
In 2009, a newly analyzed HIV sequence was reported to have greater similarity to a simian immunodeficiency virus
recently discovered in wild gorillas (SIVgor) than to SIVs from chimpanzees (SIVcpz). The virus had been isolated
from a Cameroonian woman residing in France who was diagnosed with HIV-1 infection in 2004. The scientists
reporting this sequence placed it in a proposed Group P "pending the identification of further human cases". [13][14][15]

HIV-2
HIV-2 has not been widely seen outside of Africa. The first case in the United States was in 1987.[16] Many test kits
for HIV-1 will also detect HIV-2.[17]
As of 2010, there are 8 known HIV-2 groups (A to H). Of these, only groups A and B are epidemic. Group A spread
mainly in West Africa, but also to Angola, Mozambique, Brazil,India, and very limitedly to Europe or the US. Group B
is mainly confined to West Africa. [18][19]Despite its relative confinement, HIV-2 should be considered in all patients
exhibiting symptoms of HIV that not only come from West Africa, but also anyone who has had any body fluid
transfer with a person from West Africa (ie. needle sharing, sexual contact, etc.). [20]
HIV-2 is closely related to simian immunodeficiency virus endemic in sooty mangabeys (Cercocebus atys atys)
(SIVsmm), a monkey species inhabiting the forests of Littoral West Africa. Phylogenetic analyses show that the virus
most closely related to the two strains of HIV-2 which spread considerably in humans (HIV-2 groups A and B) is the
SIVsmm found in the sooty mangabeys of the Tai forest, in western Ivory Coast.[18]

There are six additional known HIV-2 groups, each having been found in just one person. They all seem to derive
from independent transmissions from sooty mangabeys to humans. Groups C and D have been found in two people
from Liberia, groups E and F have been discovered in two people from Sierra Leone, and groups G and H have
been detected in two people from the Ivory Coast. Each of these HIV-2 strains, for which humans are
probably dead-end hosts, is most closely related to SIVsmm strains from sooty mangabeys living in the same
country where the human infection was found.[18][19]
Diagnosis
HIV-2 diagnosis can be made when a patient has no symptoms but positive blood work indicating the individual has
HIV. The Multispot HIV-1/HIV-2 Rapid Test is currently the only FDA approved method for such differentiation
between the two viruses. Recommendations for the screening and diagnosis of HIV has always been to use enzyme
immunoassays that detect HIV-1, HIV-1 group O, and HIV-2.[20] When screening the combination, if the test is
positive followed by an indeterminate HIV-1 western blot, a follow up test, such as amino acid testing, must be
performed to distinguish which infection is present. [21]According to the NIH, a differential diagnosis of HIV-2 should be
considered when a person is of West African descent or has had sexual contact or shared needles with such a
person. West Africa is at the highest risk as it is the origin of the virus.
Treatments
HIV-2 has been found to be less pathogenic than HIV-1. The mechanism of HIV-2 is not clearly defined, nor the
difference from HIV-1, however the transmission rate is much lower in HIV-2 than HIV-1. Both infections can lead to
AIDS in affected individuals and both can mutate to develop drug resistance. [20] Disease Monitoring in patients with
HIV-2 includes clinical evaluation and CD4 cell counts, while treatment includes Anti-Retroviral Therapy (ART),
Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Protease Inhibitors (PI), and Non-Nucleoside Reverse
Trascriptase Inhibitors (NNRTIs) with the addition of CCR5 co-receptor antagonists and fusion inhibitors. [22] Choice of
initial and/or second-line therapy for HIV-2 has not yet been defined. HIV-2 appears to be resistant to NNRTIs
intrinsically, but may be sensitive to NRTIs, though the mechanism is poorly understood. Protease inhibitors have
shown variable effect, while integrase inhibitors are also being evaluated. Combination regimens of the above listed
therapies are being looked into as well, also showing variable effect depending on the types of therapies combined.
While the mechanisms are not clearly understood for HIV-1 and HIV-2, it is known that they use different pathways
and patterns, making the algorithms used to evaluate HIV-1 resistance-associated mutations irrelevant to HIV-2.
[20]
Each virus can be contracted individually, or they can be contracted together in what is referred to as co-infection.
HIV-2 seems to have lower mortality rates than HIV-1 alone or the co-infection. In co-infection, however, this is
largely dependent on which virus was contracted first. HIV-1 tends to out compete HIV-2 for disease progression.
Co-infection seems to be a growing problem globally as time progresses, with most cases being identified in West
African countries, as well as some cases in the US.[22]
Pregnancy[
If a pregnant mother is exposed, screening is performed as normal. If HIV-2 is present, a number of perinatal ART
drugs may be given as a prophylactic to lower the risk of mother-to-child transmission. After the child is born, a
standard 6-week regimen of these prophylactics should be initiated. Breast milk may also contain particles of HIV-2;
therefore, breastfeeding is strictly advised against. [21]

Evolution
The AIDS virus is evolving to a milder form but is "an awfully long way" from no longer being deadly.[23]

Drug resistance mutations

Isolates of HIV-1 and HIV-2 with resistance to antiretroviral drugs arise through genetic mutations, which have been
tracked and analyzed. The Stanford HIV Drug Resistance Database and the International AIDS Society publish lists
of the most important of these; first year listing 80 common mutations, and the latest year 93 common mutations,
and made available through the Stanford HIV RT and Protease Sequence Database.