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Updated: Apr 16, 2026

Prediction of HIV-1 Coreceptor Usage Tropism by Sequence Analysis using a Genotypic Approach
Published on: December 1, 2011
Viremic control and viral coreceptor usage in two HIV-1-infected persons homozygous for CCR5 Δ32
Timothy J Henrich1, Emily Hanhauser, Zixin Hu
1aBrigham and Women's Hospital bHarvard Medical School, Boston, Massachusetts, USA cInfektionsmedizinisches Centrum Hamburg dInfektionsdiagnostik Labor Lademannbogen, Hamburg, Germany eUniversity of California, San Francisco fRagon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
Objectives:
To determine viral and immune factors involved in transmission and control of HIV-1 infection in persons without functional CCR5.
Design:
Understanding transmission and control of HIV-1 in persons homozygous for CCR5(Δ32) is important given efforts to develop HIV-1 curative therapies aimed at modifying or disrupting CCR5 expression.
Methods:
We identified two HIV-infected CCR5(Δ32/Δ32) individuals among a cohort of patients with spontaneous control of HIV-1 infection without antiretroviral therapy and determined coreceptor usage of the infecting viruses. We assessed genetic evolution of full-length HIV-1 envelope sequences by single-genome analysis from one participant and his sexual partner, and explored HIV-1 immune responses and HIV-1 mutations following virologic escape and disease progression.
Results:
Both participants experienced viremia of less than 4000 RNA copies/ml with preserved CD4(+) T-cell counts off antiretroviral therapy for at least 3.3 and 4.6 years after diagnosis, respectively. One participant had phenotypic evidence of X4 virus, had no known favorable human leukocyte antigen alleles, and appeared to be infected by minority X4 virus from a pool that predominately used CCR5 for entry. The second participant had virus that was unable to use CXCR4 for entry in phenotypic assay but was able to engage alternative viral coreceptors (e.g., CXCR6) in vitro.
Conclusion:
Our study demonstrates that individuals may be infected by minority X4 viruses from a population that predominately uses CCR5 for entry, and that viruses may bypass traditional HIV-1 coreceptors (CCR5 and CXCR4) completely by engaging alternative coreceptors to establish and propagate HIV-1 infection.
Insights
Individuals with CCR5(Δ32/Δ32) can be infected by HIV-1 using alternative coreceptors like CXCR6. This finding is crucial for developing new HIV-1 therapies targeting viral transmission and control.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Understanding HIV-1 transmission and control is vital for developing curative therapies.
- CCR5 is a key coreceptor for HIV-1 entry, and CCR5(Δ32/Δ32) individuals are generally protected.
- Efforts to develop HIV-1 curative therapies focus on modifying or disrupting CCR5 expression.
Purpose of the Study:
- To investigate viral and immune factors in HIV-1 transmission and control among individuals lacking functional CCR5.
- To determine coreceptor usage of infecting HIV-1 strains in CCR5(Δ32/Δ32) individuals.
- To explore HIV-1 evolution and immune responses in the context of alternative coreceptor usage.
Main Methods:
- Identified two HIV-infected CCR5(Δ32/Δ32) individuals with spontaneous HIV-1 control.
- Determined coreceptor usage of infecting viruses through phenotypic assays.
- Analyzed genetic evolution of HIV-1 envelope sequences and assessed immune responses.
Main Results:
- Both participants maintained low viremia and preserved CD4(+) T-cell counts without antiretroviral therapy.
- One participant was infected by minority X4 virus, while the predominant viral population used CCR5.
- The second participant's virus utilized alternative coreceptors, such as CXCR6, for entry.
Conclusions:
- HIV-1 can infect individuals lacking functional CCR5 by utilizing minority X4 variants or alternative coreceptors.
- Viruses can bypass CCR5 and CXCR4 by engaging other coreceptors for HIV-1 infection.
- This highlights novel pathways for HIV-1 transmission and potential targets for therapeutic interventions.
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