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 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).1 Many of these new strains do not survive for long, but those which 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).

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.2,3

Where are the different subtypes and CRFs found?
The HIV-1 subtypes and CRFs are very unevenly distributed throughout the world, with the most widespread being subtypes B and C.

Subtype C is largely predominant in southern and eastern Africa, India and Nepal. It has caused the world's worst HIV epidemics and is responsible for around half of all infections.

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 A and CRF A/G predominate in west and central Africa, with subtype A possibly also causing much of the Russian epidemic4 . Subtype D is generally limited to east and central Africa; A/E is prevalent in south-east Asia, but originated in central Africa; F has been found in central Africa, south America and eastern Europe; G and A/G have been observed in western and eastern 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.

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
Are there 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.5,6 However, this theory has not been conclusively proven.7,8

More recent studies have looked for variation between subtypes in rates of mother-to-child transmission. It has been claimed that such transmission is more common with subtype D than subtype A9, and that subtype C is more often transmitted than either D or A10 .

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 occured 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.11,12

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.

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."13 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.14 Rapid tests which can detect HIV-2 are also now available.15

What are the 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-2.16

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 occurance 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. To learn more about efforts to develop a vaccine for AIDS, visit the website of the International AIDS Vaccine Initiative.

This page was written by Rob Noble, November 2004.

Sources
UNAIDS Questions and Answers II, Section I, July 2004.
"HIV-1 subtype distribution and the problem of drug resistance" by Mark A. Wainberg, AIDS 2004 Volume 18 Supplement 3, 3 June 2004.
References
1 "Recombination of HIV: An Important Viral Evolutionary Strategy" by Burke DS, Emerging Infectious Diseases Vol 3 Number 3, July-September 1997.
2 "The Circulating Recombinant Forms (CRFs)", Los Alamos National Laboratory web site, http://www.hiv.lanl.gov/content/hiv-db/CRFs/CRFs.html, accessed 15th November 2004.
3 "An Isolate of Human Immunodeficiency Virus Type 1 Originally Classified as Subtype I Represents a Complex Mosaic Comprising Three Different Group M Subtypes (A, G, and I)" by Feng G, Robertson DL, Carruthers CD et al, Journal of Virology Volume 72 Number 12, December 1998.
4 "Temporal trends in the HIV-1 epidemic in Russia: predominance of subtype A" by Bobkov AF, Kazennova EV, Selimova LM et al, J Med Virol, October 2004.
5 "In vivo identification of Langerhans and related dendritic cells infected with HIV-1 subtype E in vaginal mucosa of asymptomatic patients" by Bhoopat L, Eiangleng L, Rugpao S et al, Mod Pathol. Deceber 2001.
6 "Retroviral vaccines: challenges for the developing world" by Essex M, AIDS Res Hum Retroviruses, 20 March 1996.
7 "Human immunodeficiency virus type 1 strains of subtypes B and E replicate in cutaneous dendritic cell-T-cell mixtures without displaying subtype-specific tropism" by Pope M, Frankel SS, Mascola JR et al, J Virol, October 1997.
8 "Langerhans cell tropism of human immunodeficiency virus type 1 subtype A through F isolates derived from different transmission groups" by Dittmar MT, Simmons G, Hibbitts S et al, J Virol, October 1997.
9 "Genetic diversity of HIV-1 in western Kenya: subtype-specific differences in mother-to-child transmission" by Yang, Li, Newman et al, AIDS 2003 Volume 17 Number 11, 25 July 2003.
10 "Preferential in-utero transmission of HIV-1 type C as compared to HIV-1 subtype A or D" by Renjifo B, Gilbert P, Chaplin B et al, AIDS 2004 Volume 18 Number 12, 20 August 2004.
11 "HIV-1 superinfection and viral diversity" by Gross KL, Porco TC and Grant RM, AIDS 2004 Volume 18 Number 11, 23 July 2004.
12 "HIV-1 superinfections: omens for vaccine efficacy?" by Fultz PN, AIDS 2004 Volume 18 Number 1, 2 January 2004.
13 " Revised Guidelines for HIV Counseling, Testing, and Referral", Morbidity and Mortality Weekly Report 50(RR19);1-58, 9 November 2001.
14 "Diagnosis of Human Immunodeficiency Virus Type 1 Infection with Different Subtypes Using Rapid Tests" by Phillips S, Granade TC, Pau C-P et al, Clinical and Diagnostic Laboratory Immunology, July 2000.
15 " OraQuick Rapid HIV Test for Oral Fluid – Frequently Asked Questions ", Centers for Disease Control & Prevention, 2 November 2004.
16 " Human Immunodeficiency Virus Type 2", CDC website, accessed 23 November 2004.

This copyrighted article is courtesy of AVERT