Program in Molecular Medicine; Department of Microbiology and Physiological Systems; Department of Obstetrics and Gynecology
Allergy and Immunology | Immune System Diseases | Immunology and Infectious Disease | Infectious Disease | Obstetrics and Gynecology | Virology | Virus Diseases
BACKGROUND: HIV-1 variants carrying non-macrophage-tropic HIV-1 R5 envelopes (Envs) are predominantly transmitted and persist in immune tissue even in AIDS patients who have highly macrophage-tropic variants in the brain. Non-macrophage-tropic R5 Envs require high levels of CD4 for infection contrasting with macrophage-tropic Envs, which can efficiently mediate infection of cells via low CD4. Here, we investigated whether non-macrophage-tropic R5 Envs from the acute stage of infection (including transmitted/founder Env) mediated more efficient infection of ectocervical explant cultures compared to non-macrophage-tropic and highly macrophage-tropic R5 Envs from late disease.
RESULTS: We used Env+ pseudovirions that carried a GFP reporter gene to measure infection of the first cells targeted in ectocervical explant cultures. In straight titrations of Env+ pseudovirus supernatants, mac-tropic R5 Envs from late disease mediated slightly higher infectivities for ectocervical explants although this was not significant. Surprisingly, explant infection by several T/F/acute Envs was lower than for Envs from late disease. However, when infectivity for explants was corrected to account for differences in the overall infectivity of each Env+ pseudovirus (measured on highly permissive HeLa TZM-bl cells), non-mac-tropic early and late disease Env+ pseudoviruses mediated significantly higher infection. This observation suggests that cervical tissue preferentially supports non-mac-tropic Env+ viruses compared to mac-tropic viruses. Finally, we show that T-cells were the main targets for infection regardless of whether explants were stimulated with T-cell or monocyte/macrophage cytokines. There was no evidence of macrophage infection even for pseudovirions carrying highly mac-tropic Envs from brain tissue or for the highly mac-tropic, laboratory strain, BaL, which targeted T-cells in the explant tissue.
CONCLUSIONS: Our data support ectocervical tissue as a favorable environment for non-mac-tropic HIV-1 R5 variants and emphasize the role of T-cells as initial targets for infection even for highly mac-tropic variants.
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Citation: Retrovirology. 2015 Jun 9;12:48. doi: 10.1186/s12977-015-0176-2. Link to article on publisher's site
DOI of Published Version
Ectocervical explants, HIV-1 envelopes, Tropism, T-cells, Macrophages
Peters, Paul J.; Gonzalez-Perez, Maria Paz; Musich, Thomas A.; Moore Simas, Tiffany A.; Lin, Rongheng; Morse, Abraham N.; Shattock, Robin J.; Derdeyn, Cynthia A.; and Clapham, Paul R., "Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes" (2015). Open Access Articles. 2572.
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