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  • Review Article
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The causes and consequences of HIV evolution

Nature Reviews Genetics volume 5, pages 52–61 (2004)Cite this article

Key Points

  • The present genetic diversity of HIV is the result of multiple cross-species transfers to humans from African non-human primates.

  • HIV-1 has its origin in chimpanzees and is the result of three separate transfers to humans; by contrast, HIV-2 is most closely related to strains in the sooty mangabey and is the result of at least four transfers.

  • The most recent common ancestor of HIV-1 group M (the virus that causes the vast majority of infections globally) is estimated to have existed in the 1930s, although more 'fossil' viruses are needed to confirm this.

  • HIV-1 subtypes arise as the consequence of founder events and incomplete sampling.

  • Over the course of an infection, positive natural selection is the dominant mode of HIV evolution within a single patient.

  • Over the epidemic as a whole, stochastic processes are more important for the evolution of the virus between patients. There is little evidence that fitness differences among strains determine their population structure and distribution.

  • Genetic recombination is a fundamental mechanism for the evolution of HIV.

  • The development of drug treatments has greatly extended life expectancy and quality of life for those who are HIV positive but the development of drug resistance has been a major setback.

  • Recombination can rapidly bring together resistance mutations for multiple drugs during combination therapy.

  • The development of a vaccine for HIV has been a frustratingly slow process with the few candidate vaccines that have made it to phase III trials demonstrating no efficacy.

  • The high rate of evolution means that the pattern of diversity of HIV is changing at an alarming rate.Vaccines are therefore aiming at a constantly moving target.

Abstract

Understanding the evolution of the human immunodeficiency virus (HIV) is crucial for reconstructing its origin, deciphering its interaction with the immune system and developing effective control strategies. Although it is clear that HIV-1 and HIV-2 originated in African primates, dating their transmission to humans is problematic, especially because of frequent recombination. Our ability to predict the spread of drug-resistance and immune-escape mutations depends on understanding how HIV evolution differs within and among hosts and on the role played by positive selection. For this purpose, extensive sampling of HIV genetic diversity is required, and is essential for informing the design of HIV vaccines.

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Figure 1: Key aspects of the HIV life cycle.
Figure 2: Evolutionary history of the primate lentiviruses.
Figure 3: The phylogenesis of HIV.
Figure 4: Contrasting patterns of intra- and inter-host evolution of HIV.
Figure 5: Multiple drug resistance induced by recombination.

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Acknowledgements

We thank O. Pybus and D. Robertson for some useful discussion, and A. Rodrigo and two anonymous referees for constructive comments on the draft of this manuscript. Support in the form of a research fellowship from the Royal Society (to A.R.), from the 'Ramón y Cajal' programme of the Spanish government (to D.P.), and from a National Institutes of Health grant (to K.A.C and D.P.) is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK

    Andrew Rambaut & Edward C. Holmes

  2. Departamento de Bioquímica, Genética e Inmunología, Facultad de Ciencias, Universidad de Vigo, Vigo, 36200, Spain

    David Posada

  3. Department of Microbiology and Molecular Biology, Brigham Young University, Provo, 84602, Utah, USA

    Keith A. Crandall

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Correspondence to Edward C. Holmes.

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Competing interests

Andrew Rambaut, David Posada and Keith A. Crandall have undertaken consultancy work for VaxGen, which involved genetic analysis of HIV sequences after the completion of the Phase III trials. Edward C. Holmes has no competing interests.

Related links

Related links

DATABASES

CDC database of infectious diseases

AIDS

GenBank

HIV-1

HIV-2

SIVcpz

SIVgsn

SIVsm

LocusLink

CCR5

CD4

CXCR4

FURTHER INFORMATION

HIV drug resistance databases

HIV drug resistance databases

HIV sequence database

Software and links for estimating rates of viruses

Software and links for estimating recombination

UNAIDS AIDS epidemic update 2003

VaxGen

Glossary

T-HELPER LYMPHOCYTE CELL

A type of lymphocyte that alerts the immune system to produce other cells as a response against a specific infection.

REVERSE TRANSCRIPTASE

An enzyme that is used by retroviruses and retrotransposons to synthesize DNA from an RNA template.

MAXIMUM LIKELIHOOD METHOD

A method that selects the tree that has the highest probability of explaining the sequence data, under a specific model of substitution (changes in the nucleotide or amino-acid sequence).

VIRULENCE

The ability to cause disease by breaking down the protective mechanisms of the host.

MOLECULAR CLOCK

The principle that any gene or protein has a near-constant rate of evolution in all branches of a clade, which means that the amount of sequence divergence between two sequences will be proportional to the amount of time elapsed since their shared ancestor existed.

FOUNDER EFFECTS

A situation in which a new population is founded by a small number of incoming individuals. Similar to a bottleneck, the founder effect severely reduces genetic diversity, increasing the effect of random drift.

VIRION

A mature virus particle, consisting of the genome enclosed in a protein shell and constituting the infectious form of the virus.

IMMUNE SELECTION

The process of natural selection of those virus variants that can successfully evade or manipulate the immune system.

GENETIC DRIFT

Changes in the frequency of a genetic variant in a population owing to chance alone.

EFFECTIVE POPULATION SIZE

(Ne). Formulated by Wright in 1931, Ne reflects the size of an idealized population that would experience drift in the same way as the actual (census) population. Ne can be lower than census population size owing to various factors, including a history of population bottlenecks and reduced recombination.

FIXATION

The increase in the frequency of a genetic variant in a population to 100%.

GLYCAN SHIELD

A continuously evolving pattern of glycosolation of the HIV envelope protein that hinders antibody binding but does not reduce viral fitness.

CYTOTOXIC T LYMPHOCYTES

A type of lymphocyte that can destroy virus-infected cells.

NONSYNONYMOUS SUBSTITUTION

A change in nucleotide sequence that alters the encoded amino acid.

SYNONYMOUS SUBSTITUTION

A nucleotide change in a DNA sequence that does not result in a change in the encoded amino acid.

SYNCYTIUM

A multinucleate cell in which the nuclei are not separated by cell membranes.

CHEMOKINES

Small molecules that have a central role in inflammatory responses and trigger migration and activation of phagocytic cells and lymphocytes.

NEIGHBOUR-JOINING METHOD

An algorithm that uses genetic distances to construct a phylogeny by the sequential addition of taxa.

BOTTLENECK

A severe reduction in population size that causes the loss of genetic variation. The role of random drift is increased, whereas the power of selection is reduced, by bottlenecks.

HLA HAPLOTYPE

The particular pattern of alleles at the human major histocompatibility complex (MHC) loci, which defines which antigens are recognized by T cells.

ADAPTIVE PEAKS

If all morphological variation or all possible phenotypes are considered as a landscape, some will have particularly high fitness (peaks).

STERILIZING IMMUNITY

An immune response whereby the infection is entirely prevented or rapidly cleared, leaving no detectable trace.

SUPERINFECTION

The infection by a second strain of virus in a patient that is already infected.

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Rambaut, A., Posada, D., Crandall, K. et al. The causes and consequences of HIV evolution. Nat Rev Genet 5, 52–61 (2004). https://doi.org/10.1038/nrg1246

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