Amphipathic domains in the C terminus of the transmembrane protein (gp41) permeabilize HIV-1 virions: a molecular mechanism underlying natural endogenous reverse transcription.
Reverse transcription of HIV-1, without detergent or amphipathic peptide-induced permeability of the viral envelope, has been demonstrated to occur in the intact HIV-1 virion. In this report, we demonstrate that the amphipathic domains in the C terminus of the transmembrane glycoprotein (gp41) account for the natural permeability of the HIV-1 envelope to deoxyribonucleoside triphosphates, the substrates for DNA polymerization. In addition, nonphysiological deoxyribonucleoside triphosphates, such as 3'-azido-3'-deoxythymidine 5'-triphosphate and 3'-deoxythymidine 5'-triphosphate, can also penetrate the viral envelope, incorporate into, and irreversibly terminate reverse transcripts. As a result, viral infectivity is potently inhibited. Since the lentiviral envelope with these newly demonstrated characteristics can serve as a delivery pathway for anti-reverse transcription agents, we propose a unique strategy to prevent HIV-1 interand, possibly, intrahost transmission.
Dorrance H. Hamilton Laboratories, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
H
H
Zhang
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G
Dornadula
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P
Alur
M A
MA
Laughlin
R J
RJ
Pomerantz
D000818:Animals; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D010539:Permeability / Q000187:drug effects; D051381:Rats; D013942:Thymine Nucleotides / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014771:Virion / Q000187:drug effects*
D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D003848:Deoxyguanine Nucleotides; D015700:HIV Envelope Protein gp41; D013942:Thymine Nucleotides; C024107:2'-deoxycytidine 5'-triphosphate; C029603:deoxyguanosine triphosphate; D054303:HIV Reverse Transcriptase; C026600:2'-deoxyadenosine triphosphate; C024157:thymidine 5'-triphosphate