Transmission of highly virulent CXCR4 tropic HIV-1 through the mucosal route in an individual with a wild-type CCR5 genotypeResearch in context
Manukumar Honnayakanahalli Marichannegowda,
Saini Setua,
Meera Bose,
Eric Sanders-Buell,
David King,
Michelle Zemil,
Lindsay Wieczorek,
Felisa Diaz-Mendez,
Nicolas Chomont,
Rasmi Thomas,
Leilani Francisco,
Leigh Anne Eller,
Victoria R. Polonis,
Sodsai Tovanabutra,
Alonso Heredia,
Yutaka Tagaya,
Nelson L. Michael,
Merlin L. Robb,
Hongshuo Song
Affiliations
Manukumar Honnayakanahalli Marichannegowda
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Saini Setua
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Meera Bose
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Eric Sanders-Buell
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
David King
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Michelle Zemil
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Lindsay Wieczorek
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Felisa Diaz-Mendez
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Nicolas Chomont
Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Canada
Rasmi Thomas
Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Leilani Francisco
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Leigh Anne Eller
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Victoria R. Polonis
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Sodsai Tovanabutra
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Alonso Heredia
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Yutaka Tagaya
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
Nelson L. Michael
Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Merlin L. Robb
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
Hongshuo Song
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA; Corresponding author. Institute of Human Virology, University of Maryland School of Medicine, 725 W. Lombard Street, Room N248, Baltimore, MD, 21201, USA.
Summary: Background: Nearly all transmitted/founder (T/F) HIV-1 are CCR5 (R5)-tropic. While previous evidence suggested that CXCR4 (X4)-tropic HIV-1 are transmissible, virus detection and characterization were not at the earliest stages of acute infection. Methods: We identified an X4-tropic T/F HIV-1 in a participant (40700) in the RV217 acute infection cohort. Coreceptor usage was determined in TZM-bl cell line, NP-2 cell lines, and primary CD4+ T cells using pseudovirus and infectious molecular clones. CD4 subset dynamics were analyzed using flow cytometry. Viral load in each CD4 subset was quantified using cell-associated HIV RNA assay and total and integrated HIV DNA assay. Findings: Participant 40700 was infected by an X4 tropic HIV-1 without CCR5 using ability. This participant experienced significantly faster CD4 depletion compared to R5 virus infected individuals in the same cohort. Naïve and central memory (CM) CD4 subsets declined faster than effector memory (EM) and transitional memory (TM) subsets. All CD4 subsets, including the naïve, were productively infected. Increased CD4+ T cell activation was observed over time. This X4-tropic T/F virus is resistant to broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 regions, while most of the R5 T/F viruses in the same cohort are sensitive to the same panel of bNAbs. Interpretation: X4-tropic HIV-1 is transmissible through mucosal route in people with wild-type CCR5 genotype. The CD4 subset tropism of HIV-1 may be an important determinant for HIV-1 transmissibility and virulence. Funding: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine.
