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Journal of Virology, July 1999, p. 5698-5706, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Variable Constraints on the Principal Immunodominant Domain of the Transmembrane Glycoprotein of Human Immunodeficiency Virus Type 1

Rastine Merat,1,dagger Herve Raoul,2 Thierry Leste-Lasserre,1 Pierre Sonigo,1,* and Gianfranco Pancino1,Dagger

Génétique des Virus (ICGM-CNRS UPR0415), Institut Cochin de Génétique Moléculaire, 75014 Paris,1 and Commissariat à l'Energie Atomique, Service de Neurovirologie, DSV/DRN/SSA, 92265 Fontenay aux Roses Cedex,2 France

Received 28 October 1998/Accepted 16 March 1999

Lentiviruses have in their transmembrane glycoprotein (TM) a highly immunogenic structure referred to as the principal immunodominant domain (PID). The PID forms a loop of 5 to 7 amino acids between two conserved cysteines. Previous studies showed that envelope (Env) glycoprotein functions of feline immunodeficiency virus (FIV) could be retained after extensive mutation of the PID loop sequence, in spite of its high conservation. In order to compare Env function in different lentiviruses, either random mutations were introduced in the PID loop sequence of human immunodeficiency virus type 1 (HIV-1) or the entire HIV-1 PID loop was replaced by the corresponding PID loop of FIV or simian immunodeficiency virus (SIV). In the macrophage-tropic HIV-1 ADA Env, mutations impaired the processing of the gp160 Env precursor, thereby abolishing viral infectivity. However, 6 of the 108 random Env mutants that were screened retained the capacity to induce cell membrane fusion. The SIV and FIV sequences and five random mutations were then introduced in the context of T-cell-line-adapted HIV-1 LAI which, although phenotypically distant from HIV-1 ADA, has an identical PID loop sequence. In contrast to the situation for HIV-1 ADA mutants, the cleavage of the Env precursor was unaffected in most HIV-1 LAI mutants. Such mutations, however, resulted in increased shedding of the gp120 surface glycoprotein (SU) from the gp41 TM. The HIV-1 LAI Env mutants showed high fusogenic efficiency. Three Env mutants retained the capacity to mediate virus entry in target cells, although less efficiently than the wild-type Env, and allowed the reconstitution of infectious molecular clones. These results indicated that in HIV-1, like FIV, the conserved PID sequence can be changed without impairing Env function. However, functional constraints on the PID of HIV-1 vary depending on the structural context of Env, presumably in relation to the role of the PID in the interaction of the SU and TM subunits and the stability of the Env complex.

* Corresponding author. Mailing address: Institut Cochin de Génétique Moléculaire, Génétique des Virus, 22 rue Méchain, 75014 Paris, France. Phone: (33)-01 40 51 64 15. Fax: (33)-01 40 51 72 10. E-mail: sonigo{at}cochin.inserm.fr.

dagger Present address: Policlinique de Dermatologie, Hôpital Saint-Louis, 75010 Paris, France.

Dagger Present address: Laboratoire de Biologie des Rétrovirus, Institut Pasteur, 75724 Paris Cedex 15, France.

Journal of Virology, July 1999, p. 5698-5706, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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