Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection
Open accessAbstract
Rare individuals have been multiply exposed to HIV-1 but remain uninfected. The CD4+ T-cells of two of these individuals, designated EU2 and EU3, are highly resistant in vitro to the entry of primary macrophagetropic virus but are readily infectable with transformed T-cell line adapted viruses. We report here on the genetic basis of this resistance. We found that EU2 and EU3 have a homozygous defect in CKR-5, the gene encoding the recently described coreceptor for primary HIV-1 isolates. These individuals appear to have inherited a defective CKR-5 allele that contains an internal 32 base pair deletion. The encoded protein is severely truncated and cannot be detected at the cell surface. Surprisingly, this defect has no obvious phenotype in the affected individuals. Thus, a CKR-5 allele present in the human population appears to protect homozygous individuals from sexual transmission of HIV-1. Heterozygous individuals are quite common (approximately 20%) in some populations. These findings indicate the importance of CKR-5 in HIV-1 transmission and suggest that targeting the HIV-1-CKR-5 interaction may provide a means of preventing or slowing disease progression.
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Gene loss in humans or human individuals can be adaptive by enhancing protection against pathogenic bacteria or diseases such as plasmodium and HIV infections, and sepsis.
“These studies also revealed that gene loss in humans or human individuals can be adaptive by enhancing protection against pathogenic bacteria or diseases such as plasmodium and HIV infections, and sepsis17–20.”
From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [17]
The Abstract and Discussion report that a CKR-5 deletion appears to protect two multiply exposed individuals from HIV-1 infection. The Discussion also describes a loss-of-expression DARC allele that provides resistance to Plasmodium vivax, but treats a selective advantage for the CKR-5 deletion as possible rather than established. The paper does not address protection against pathogenic bacteria or sepsis. (LLM, conf=0.88)
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- Authors
- Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlmann, H., Koup, R. A., & Landau, N. R.
- Affiliations
- Aaron Diamond AIDS Research Center (US)
- Massachusetts General Hospital (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Landau, Nathaniel R
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1996-08
- Volume
- 86
- Issue
- 3
- Pages
- 367-377
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2090630729
- Cited by
- 3,074
- References
- 1
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 35 · 2023: 38 · 2022: 48 · 2021: 58 · 2020: 64 · 2019: 68 · 2018: 55 · 2017: 80 · 2016: 67 · 2015: 91 · 2014: 95 · 2013: 95 · 2012: 122
- FWCI
- 52.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- National Cancer Institute (R01CA072149)
- National Institute of Allergy and Infectious Diseases (R29AI036057, R01AI035522)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1, CCR5, HIV-1 coreceptor, HIV-1 resistance, CD4+ T cells, macrophage-tropic HIV-1, sexual transmission, HIV-1 transmission, HIV-1 prevention
- MeSH terms
- Alleles, Amino Acid Sequence, Base Sequence, DNA, Viral, Homozygote, Humans, Immunity, Innate, Molecular Sequence Data, Transcription, Genetic, Virus Replication, Restriction Mapping, HIV-1, HIV Infections, Receptors, HIV, Sequence Deletion, DNA, Complementary, Receptors, Cytokine, Receptors, CCR5
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