title: Mechanisms of nonrandom human immunodeficiency virus type 1 infection and double infection: preference in virus entry is important but is not the sole factor.
abstract: We previously demonstrated that human immunodeficiency virus type 1 (HIV-1) infection is nonrandom and that double infection occurs more frequently than predicted from random events. To probe the possible mechanisms for nonrandom infection, we examined the role of HIV-1 entry pathways by using viruses pseudotyped with either CCR5-tropic HIV-1 Env or vesicular stomatitis virus G protein (VSV G). These two proteins use different receptors and entry pathways. We found that regardless of the protein used, double infection occurred more frequently than random events, indicating nonrandom HIV-1 infection in both entry pathways. However, the frequency of double infection differed significantly, depending on the envelope protein. In primary CD4(+) T cells, double infection occurred most frequently when both viruses had CCR5-tropic HIV-1 Env and least frequently when the two viruses had different envelopes. These results indicated that the preference in virus entry was a significant but not the only factor contributing to nonrandom double infection. Furthermore, we demonstrated that the CD4 expression level in primary T cells affects their susceptibility to CCR5-tropic HIV-1 infection but not VSV G-pseudotyped HIV-1 infection. We have also examined infection with two viruses pseudotyped with CCR5- or CXCR4-tropic HIV-1 Env and have found that double infection occurred more frequently than random events. These results indicate that coreceptor usage is not a barrier to recombination between the two virus populations. In our previous study, we also demonstrated nonrandom double infection via dendritic cell (DC)-mediated HIV-1 transmission. To test our hypothesis that multiple HIV-1 virions are transmitted during DC-T-cell contact, we used two populations of DCs, each capturing one vector virus, and added both DC populations to T cells. We observed a decreased frequency of double infection compared with experiments in which DCs captured both viruses simultaneously. Therefore, these results support our hypothesis that multiple virions are transmitted from DCs to T cells during cell-mediated HIV-1 transmission.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Chen
authors.forename: Que
authors.initials: Q
authors.lastname: Dang
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Pathak
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Douglas
authors.initials: D
authors.lastname: Powell
authors.forename: Wei-Shau
authors.initials: WS
authors.lastname: Hu
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000821:virology; D015686:Gene Products, env / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D019713:Receptors, CCR5 / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D015728:Receptors, HIV / Q000502:physiology; D014759:Viral Envelope Proteins / Q000502:physiology; D054299:env Gene Products, Human Immunodeficiency Virus
chemical_list: D015704:CD4 Antigens; C028391:G protein, vesicular stomatitis virus; D015686:Gene Products, env; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D014759:Viral Envelope Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1