HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+T-cells than envelopes highly adapted for macrophages

• Authors: Thomas Musich, University of Massachusetts Medical School; Olivia O'Connell, University of Massachusetts Medical School; Maria Paz Gonzalez-Perez, University of Massachusetts Medical School; Cynthia Derdeyn, Emory University; Paul J. Peters, University of Massachusetts Medical School; Paul R. Clapham, University of Massachusetts Medical School
• Journal Title: Retrovirology
• Volume: Volume 12, Number 1
• Publisher: BioMed Central | 2015-03-14, Pages 25-25
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12977-015-0141-0
• Subjects: Biology, Virology; Biology, Microbiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Virology; HIV-1; Tropism; Macrophage-tropism; Non-macrophage-tropism; Dendritic cells; Trans-infection; Envelope; T-cells; Macrophages; Functionality; IMMUNODEFICIENCY-VIRUS TYPE-1; MONOCYTE-DERIVED MACROPHAGES; INFECTIOUS MOLECULAR CLONES; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; CD4(+) T-CELLS; DENDRITIC CELLS; HETEROSEXUAL TRANSMISSION; LYMPHOID-TISSUES; SUBTYPE-B

Abstract

Non-mac-tropic HIV-1 R5 viruses are predominantly transmitted and persist in immune tissue even in AIDS patients who carry highly mac-tropic variants in the brain. Non-mac-tropic R5 envelopes (Envs) require high CD4 levels for infection contrasting with highly mac-tropic Envs, which interact more efficiently with CD4 and mediate infection of macrophages that express low CD4. Non-mac-tropic R5 Envs predominantly target T-cells during transmission and in immune tissue where they must outcompete mac-tropic variants. Here, we investigated whether Env+ pseudoviruses bearing transmitted/founder (T/F), early and late disease non-mac-tropic R5 envelopes mediated more efficient infection of CD4+ T-cells compared to those with highly mac-tropic Envs. Results: Highly mac-tropic Envs mediated highest infectivity for primary T-cells, Jurkat/CCR5 cells, myeloid dendritic cells, macrophages, and HeLa TZM-bl cells, although this was most dramatic on macrophages. Infection of primary T-cells mediated by all Envs was low. However, infection of T-cells was greatly enhanced by increasing virus attachment with DEAE dextran and spinoculation, which enhanced the three Env+virus groups to similar extents. Dendritic cell capture of viruses and trans-infection also greatly enhanced infection of primary T-cells. In trans-infection assays, non-mac-tropic R5 Envs were preferentially enhanced and those from late disease mediated levels of T-cell infection that were equivalent to those mediated by mac-tropic Envs. Conclusions: Our results demonstrate that T/F, early or late disease non-mac-tropic R5 Envs do not preferentially mediate infection of primary CD4+ T-cells compared to highly mac-tropic Envs from brain tissue. We conclude that non-macrophage-tropism of HIV-1 R5 Envs in vitro is determined predominantly by a reduced capacity to target myeloid cells via low CD4 rather than a specific adaptation for T-cells entry that precludes macrophage infection.