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Journal of Virology, May 2007, p. 4776-4786, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.01793-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Maintenance of Nef-Mediated Modulation of Major Histocompatibility Complex Class I and CD4 after Sexual Transmission of Human Immunodeficiency Virus Type 1{triangledown} ,{dagger}

C. M. Noviello,1,2 S. L. Kosakovsky Pond,3 M. J. Lewis,5 D. D. Richman,1,2,3,4 S. K. Pillai,2 O. O. Yang,5,6 S. J. Little,2 D. M. Smith,2,4* and J. C. Guatelli1,2,4*

Biomedical Sciences Graduate Program,1 Departments of Medicine,2 Pathology, University of California, San Diego, La Jolla, California,3 San Diego Veteran Affairs Healthcare Systems, San Diego, California,4 Department of Medicine,5 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California6

Received 17 August 2006/ Accepted 17 February 2007

Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.

* Corresponding author. Mailing address: University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Phone: (858) 552-8585. ext. 7170. Fax: (858) 552-7445. E-mail for J. C. Guatelli: jguatelli{at}ucsd.edu. E-mail for D. M. Smith: davey{at}ucsd.edu

{triangledown} Published ahead of print on 28 February 2007.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, May 2007, p. 4776-4786, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.01793-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lewis, M. J., Balamurugan, A., Ohno, A., Kilpatrick, S., Ng, H. L., Yang, O. O. (2008). Functional Adaptation of Nef to the Immune Milieu of HIV-1 Infection In Vivo. J. Immunol. 180: 4075-4081 [Abstract] [Full Text]  


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