Phenotypic properties of transmitted founder HIV-1
Abstract
Defining the virus–host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines.
Additional Information
© 2013 National Academy of Sciences. Contributed by Beatrice H. Hahn, March 5, 2013 (sent for review January 29, 2013). Published online before print March 29, 2013. We thank John Moore, Frank Kirchhoff, Paul Sharp, and Stuart Shapiro for helpful discussions; the University of Pennsylvania's Center for AIDS Research (CFAR) Human Immunology, Flow Cytometry, and Viral and Molecular Core facilities for reagents and protocols; and Patricia Crystal for artwork and manuscript preparation. This work was supported by National Institutes of Health (NIH) Grants R01 AI45378, R01 AI04088, P30 AI45008, and P30 AI27767, Center for HIV/AIDS Vaccine Immunology Grant U19 AI067854, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant UM1 AI100645, and Bill and Melinda Gates Foundation Grant 37874. N.F.P., S.S.I., and C.B.W. were supported by NIH Training Grant T32 AI07632. Author contributions: N.F.P., F.G., H.L., H.J.B., E.H.P., L.Z., S.S.I., J.M.D., A.K., B.H., A.B., F.C., J.H., T.N.D., H.D., C.O., J.C.K., and C.B.W. performed research; E.E.G., R.P.G., A.P.W., P.J.B., M.O., N.B., M.M., J.P.T., and B.K. contributed new reagents/analytic tools; and N.F.P., E.E.G., C.B.W., R.W.D., P.B., B.F.H., B.K., G.M.S., and B.H.H. wrote the paper.Attached Files
Published - PNAS-2013-Parrish-6626-33.pdf
Supplemental Material - pnas.201304288SI.pdf
Supplemental Material - sfig01.pdf
Supplemental Material - sfig02.pdf
Supplemental Material - sfig03.pdf
Supplemental Material - sfig04.pdf
Supplemental Material - sfig05.pdf
Supplemental Material - sfig06.pdf
Supplemental Material - sfig07.pdf
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Additional details
- PMCID
- PMC3637789
- Eprint ID
- 39059
- Resolver ID
- CaltechAUTHORS:20130624-144728353
- NIH
- R01 AI45378
- NIH
- R01 AI04088
- NIH
- P30 AI45008
- NIH
- P30 AI27767
- NIH
- U19 AI067854
- NIH
- UM1 AI100645
- Bill and Melinda Gates Foundation
- 37874
- NIH Predoctoral Fellowship
- T32 AI07632
- Created
-
2013-06-24Created from EPrint's datestamp field
- Updated
-
2021-11-09Created from EPrint's last_modified field