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Journal of Virology, October 2001, p. 9357-9366, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9357-9366.2001

Human Immunodeficiency Virus Type 1 N-Terminal Capsid Mutants That Exhibit Aberrant Core Morphology and Are Blocked in Initiation of Reverse Transcription in Infected Cells

Shixing Tang,1 Tsutomu Murakami,2 Beth E. Agresta,1 Stephen Campbell,3 Eric O. Freed,2 and Judith G. Levin1,*

Laboratory of Molecular Genetics, National Institute of Child Health and Human Development,1 and Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases,2 Bethesda, Maryland 20892, and HIV Drug Resistance Program, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 217023

Received 21 March 2001/Accepted 23 June 2001

A group of conserved hydrophobic residues faces the interior of the coiled-coil-like structure within the N-terminal domain of the human immunodeficiency virus type 1 (HIV-1) capsid protein (CA). It has been suggested that these residues are important for maintaining stable structure and functional activity. To investigate this possibility, we constructed two HIV-1 clones, in which Trp23 or Phe40 was changed to Ala. We also constructed a third mutant, D51A, which has a mutation that destroys a salt bridge between Pro1 and Asp51. All three mutants are replication defective but produce virus particles. Mutant virions contain all of the viral proteins, although the amount and stability of CA are decreased and levels of virion-associated integrase are reduced. The mutations do not affect endogenous reverse transcriptase activity; however, the mutants are blocked in their ability to initiate reverse transcription in infected cells and no minus-strand strong-stop DNA is detected. The defect in reverse transcription is associated with striking defects in the morphology of mutant virus cores, as determined by transmission electron microscopy. Our data indicate that the mutations made in this study disrupt CA structure and prevent proper maturation of virus cores. We propose that this results in a defect in core stability or in an early postentry event preceding reverse transcription.

* Corresponding author. Mailing address: Laboratory of Molecular Genetics, NICHD, Building 6B, Room 216, NIH, Bethesda, MD 20892-2780. Phone: (301) 496-1970. Fax: (301) 496-0243. E-mail: jlevin{at}mail.nih.gov.

Journal of Virology, October 2001, p. 9357-9366, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9357-9366.2001


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