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Journal of Virology, May 2000, p. 4361-4376, Vol. 74, No. 9
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Unusual Polymorphisms in Human Immunodeficiency Virus Type 1 Associated with Nonprogressive Infection

Louis Alexander,1 Emma Weiskopf,1 Thomas C. Greenough,2 Nathan C. Gaddis,3 Marcy R. Auerbach,1 Michael H. Malim,3 Stephen J. O'Brien,4 Bruce D. Walker,5 John L. Sullivan,2 and Ronald C. Desrosiers1,*

New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 017721; Program in Molecular Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 016052; Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 191043; Laboratory of Genetic Diversity, National Cancer Institute, Frederick, Maryland 217024; and Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021145

Received 15 November 1999/Accepted 26 January 2000

Factors accounting for long-term nonprogression may include infection with an attenuated strain of human immunodeficiency virus type 1 (HIV-1), genetic polymorphisms in the host, and virus-specific immune responses. In this study, we examined eight individuals with nonprogressing or slowly progressing HIV-1 infection, none of whom were homozygous for host-specific polymorphisms (CCR5-Delta 32, CCR2-64I, and SDF-1-3'A) which have been associated with slower disease progression. HIV-1 was recovered from seven of the eight, and recovered virus was used for sequencing the full-length HIV-1 genome; full-length HIV-1 genome sequences from the eighth were determined following amplification of viral sequences directly from peripheral blood mononuclear cells (PBMC). Longitudinal studies of one individual with HIV-1 that consistently exhibited a slow/low growth phenotype revealed a single amino acid deletion in a conserved region of the gp41 transmembrane protein that was not seen in any of 131 envelope sequences in the Los Alamos HIV-1 sequence database. Genetic analysis also revealed that five of the eight individuals harbored HIV-1 with unusual 1- or 2-amino-acid deletions in the Gag sequence compared to subgroup B Gag consensus sequences. These deletions in Gag have either never been observed previously or are extremely rare in the database. Three individuals had deletions in Nef, and one had a 4-amino-acid insertion in Vpu. The unusual polymorphisms in Gag, Env, and Nef described here were also found in stored PBMC samples taken 3 to 11 years prior to, or in one case 4 years subsequent to, the time of sampling for the original sequencing. In all, seven of the eight individuals exhibited one or more unusual polymorphisms; a total of 13 unusual polymorphisms were documented in these seven individuals. These polymorphisms may have been present from the time of initial infection or may have appeared in response to immune surveillance or other selective pressures. Our results indicate that unusual, difficult-to-revert polymorphisms in HIV-1 can be found associated with slow progression or nonprogression in a majority of such cases.

* Corresponding author. Mailing address: Harvard Medical School, New England Regional Primate Research Center, 1 Pine Hill Dr., Southborough, MA 01772-9102. Phone: (508) 624-8002. Fax: (508) 460-0612. E-mail: ronald_desrosiers{at}hms.harvard.edu.

Journal of Virology, May 2000, p. 4361-4376, Vol. 74, No. 9
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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