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Bottlenecks in HIV-1 transmission: insights from the study of founder viruses

Key Points

  • Approximately 80% of HIV-1 heterosexual transmission events are established from a single transmitted/founder (T/F) virus.

  • During transmission, multiple bottlenecks reduce the viral population from the large, genetically variable population in the blood of a chronically infected donor to a single T/F virus in the newly infected recipient.

  • Recent evidence suggests that transmission of a single T/F virus results from both stochastic bottlenecks that restrict transmission of all viruses (for example, nonspecific barrier functions) and selective bottlenecks that favour transmission of viruses with specific phenotypes.

  • Understanding the bottlenecks that restrict transmission may inform targets for prevention strategies. For example, antiretrovirals can be used to suppress the viral population in infected individuals and prevent them from sexually transmitting HIV-1 (that is, 'treatment as prevention').

Abstract

HIV-1 infection typically results from the transmission of a single viral variant, the transmitted/founder (T/F) virus. Studies of these HIV-1 variants provide critical information about the transmission bottlenecks and the selective pressures acting on the virus in the transmission fluid and in the recipient tissues. These studies reveal that T/F virus phenotypes are shaped by stochastic and selective forces that restrict transmission and may be targets for prevention strategies. In this Review, we highlight how studies of T/F viruses contribute to a better understanding of the biology of HIV-1 transmission and discuss how these findings affect HIV-1 prevention strategies.

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Figure 1: The transmitted/founder virus is shaped by multiple genetic bottlenecks.
Figure 2: Compartmentalization of genital tract-specific viral lineages.
Figure 3: Selection of transmitted/founder virus phenotypes.
Figure 4: Characteristics of transmitted/founder viruses.

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Acknowledgements

This work was funded by awards from the US National Institutes of Health (U01 AI067854 (CHAVI)), and R37 AI44667 to R.S. and R37 DK049381 to M.S.C.).

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Correspondence to Sarah B. Joseph.

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Glossary

Retrovirus

A member of the family Retroviridae. Retroviruses use reverse transcriptase to convert their single-stranded RNA genome into double-stranded DNA, which is subsequently integrated into the host genome. The integrated proviral genome may be transcribed, translated and assembled into new virions.

Lentivirus

Genus of the family Retroviridae that includes HIV and simian immunodeficiency virus (SIV).

Transmitted/founder virus

(T/F virus). The virus that forms a systemic infection after being transferred from an infected individual to an uninfected individual. HIV-1 infections are typically established from a single T/F virus.

env

Gene encoding the HIV-1 Env glycoprotein. This protein is cleaved into two subunits (gp120 and gp41), which are non-covalently bound as heterodimers and organized as trimers on the virion surface. Env glycoproteins facilitate virus binding to and fusion with host cells.

Compartmentalized lineages

Virus variants found outside the blood that are genetically distinct from variants in the blood. Compartmentalized lineages evolve after many generations of independent replication in a tissue or compartment.

Transmission pairs

HIV-1 donors and the recipient that each infected. Studies of transmission pairs are useful for examining many aspects of transmission biology, including factors that influence the probability of transmission and whether transmission bottlenecks select for specific viral phenotypes.

Neutralizing antibodies

Antibodies that inactivate infectious agents after recognizing antigens on their surface.

Lectins

Carbohydrate-binding proteins capable of neutralizing viruses by binding glycans on the viral surface.

Glycosylation

The host process of attaching glycans to proteins. Glycosylation of HIV-1 Env has the effect of shielding epitopes on Env from antibody binding.

HIV subtypes

Group M HIV-1 contains multiple lineages, termed subtypes.

Autologous donor antibodies

Antibodies that are produced by the same individual who produced the viruses that they are neutralizing. May inhibit transmission by neutralizing viruses in the transmission fluid.

Heterologous antibodies

Antibodies that are produced by an individual different from the one who produced the viruses that they are neutralizing.

Pseudotyped viruses

Viruses produced in vitro using a method that allows the researcher to control the specific Env proteins expressed on the surface of the virion.

Infectious molecular clones

(IMCs). Full-length DNA clones of HIV-1 genomes capable of producing replication- competent viruses.

Cytotoxic T lymphocyte (CTL)-escape mutants

Viral variants that carry mutations in viral proteins that allow viruses to avoid detection by CTL. These mutations can reduce viral replicative fitness.

Interferon-α

(IFNα). A cytokine whose expression is rapidly upregulated after virus exposure to signal cells to create an antiviral environment. IFNα can reduce HIV-1 replication.

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Joseph, S., Swanstrom, R., Kashuba, A. et al. Bottlenecks in HIV-1 transmission: insights from the study of founder viruses. Nat Rev Microbiol 13, 414–425 (2015). https://doi.org/10.1038/nrmicro3471

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