To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC proteins from the surface of infected cells. However, class I downregulation potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E. We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E. We then identify the residues in HLA-C and HLA-E that protect them from HIV downregulation. This selective downregulation allows HIV-infected cells to avoid NK cell-mediated lysis and may represent for HIV a balance between escape from CTL and maintenance of protection from NK cells. These results suggest that subpopulations of CTL and NK cells may be uniquely suited for combating HIV.
Bibliographical noteFunding Information:
We thank Carlos Lois and members of the Baltimore and Strominger laboratories for helpful discussions, Bruce Walker, Glenn Paradis, Veronique Braud, Eric Long, and Lewis Lanier for reagents and advice on aspects of this project, and Douglas Nixon for communicating unpublished results. G. B. C. was supported by a Merck/Massachusetts Institute of Technology and Helen-Hay Whitney Fellowship, R. T. G. by a Howard Hughes Postdoctoral Research Fellowship for Physicians and a National Institutes of Health Mentored Clinical Scientist Development Award, D. D. by the Irvington Institute, O. M. by the Damon Runyon-Walter Winchell Foundation, B. K. C. by a Medical Scientist Training Program Award, and J. L. S. by National Institutes of Health grant R35CA47554. D. B. is an American Cancer Society Research Professor and was supported at the Massachusetts Institute of Technology by funds from the Ivan R. Cottrell Chair and grants from the National Institutes of Health.