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Coreceptor utilization of HIV type 1 subtype E viral isolates from Thai men with HIV type 1-infected and uninfected
Utaiwan Utaipat1, Ann Duerr, Donna L Rudolph
1HIV Immunology and Diagnostics Branch, DASTLR, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Insights
Human immunodeficiency virus type 1 (HIV-1) coreceptor usage, specifically CCR5 and CXCR4, is crucial for viral entry. This study found no association between coreceptor tropism patterns and HIV-1 transmissibility in Thai subtype E isolates.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Human immunodeficiency virus type 1 (HIV-1) entry into host cells relies on coreceptors, primarily CCR5 and CXCR4.
- Understanding viral tropism is essential for comprehending HIV-1 transmission dynamics and pathogenesis.
- Viral isolates from heterosexual transmission in Thailand, predominantly subtype E, were analyzed for coreceptor utilization.
Purpose of the Study:
- To investigate the role of viral tropism in HIV-1 transmission among heterosexual couples in Northern Thailand.
- To characterize the coreceptor usage patterns of HIV-1 isolates from infected males based on their spouse's HIV status.
Main Methods:
- Viral isolates were obtained from HIV-1-positive males (n=15) with either HIV-1-infected (RM, n=5) or HIV-1-uninfected (HM, n=10) spouses.
- Coreceptor tropism was assessed using cell-based assays (GHOST4.cl.34, MAGI-plaque assays) and replication kinetics in peripheral blood mononuclear cells.
- Sensitivity to X4-antagonistic compounds (T-22, AMD3100) and C2V3 region sequencing were performed.
Main Results:
- A minority of isolates were CCR5-tropic (3/15), while a majority were CXCR4-tropic (9/15).
- Seven of nine CXCR4-tropic isolates utilized additional coreceptors (CCR8, CCR1, CCR2b, CX3CR1), but not CCR5.
- Three isolates showed unusual coreceptor usage, replicating in CCR5(+/+) and CCR5(-/-) cells and sensitive to X4 antagonists, yet did not infect GHOST4.cl.34 cells expressing known coreceptors.
Conclusions:
- No significant structural differences were found in the C2V3 region of Thai subtype E isolates.
- The study found no association between the pattern of coreceptor usage and transmissibility in these specific HIV-1 subtype E isolates.
- Further research may be needed to fully elucidate the mechanisms of entry for isolates with atypical coreceptor utilization.
Abstract:
HIV-1 coreceptors CCR5 and CXCR4 play an important role in viral entry and pathogenesis. To better understand the role of viral tropism in HIV-1 transmission, we examined the coreceptor utilization of viral isolates obtained from men enrolled in a study of heterosexual transmission in northern Thailand. Viral isolates were obtained from HIV-1-positive males who had either HIV-1-infected spouses (RM; n = 5) or HIV-1-uninfected spouses (HM; n = 10). Viral isolates from 1 of the 5 RM males and 2 of the 10 HM males were CCR5 tropic, whereas isolates from 3 RM males and 6 of the HM male isolates were CXCR4 tropic. Of the nine X4-tropic isolates, seven also used at least one of the following coreceptors: CCR8, CCR1, CCR2b, or CX3CR1, and none employed CCR5 as an additional coreceptor. More importantly, three isolates, RM-15, HM-13, and HM-16 (one from a transmitter and two from nontransmitter), did not infect GHOST4.cl.34 cells expressing any of the known coreceptors. Further analysis using MAGI-plaque assays, which allow visualization of infected cells, revealed that RM-15 had low numbers of infected cells in MAGI-R5 and MAGI-X4 cultures, whereas HM-13 and HM-16 had high levels of plaques in MAGI-X4 cultures. Replication kinetics using activated lymphocytes revealed that these three isolates replicated in CCR5(+/+) as well as CCR5(-/-) peripheral blood mononuclear cells, suggesting that these isolates did not have an absolute requirement of CCR5 for viral entry. All three isolates were sensitive to the X4-antagonistic compounds T-22 and AMD3100. Analysis of the C2V3 region did not reveal any significant structural differences between any of the Thai subtype E isolates. Thus, there was no association between the pattern of coreceptor usage and transmissibility among these subtype E HIV-1 isolates.