Restriction of HIV type 1 infection in macrophages heterozygous for a deletion in the CC-chemokine receptor 5 gene.
Homozygosity for a 32-base pair deletion (delta32) within the CC-chemokine receptor 5 (CCR5) gene confers resistance to infection by R5-type HIV-1 isolates. To ascertain how CCR5delta32 heterozygosity influences the susceptibility of lymphocytes and macrophages to HIV-1 infection, peripheral blood lymphocytes (PBLs) and monocyte-derived macrophages (MDMs) from three HIV-1-uninfected CCR5delta32 heterozygous infants and three HIV-1-uninfected CCR5 wild-type homozygous infants were exposed to two R5-type primary isolates. HIV-1 infection was monitored by DNA-PCR and p24 antigen determination; CCR5 and CCR5delta32 transcripts were quantified by competitive reverse transcription-PCR. Wild-type homozygous MDMs and PBLs and heterozygous PBLs were infected by both viral isolates, albeit with different efficiencies, but heterozygous MDMs showed restriction to HIV-1 infection. Lower levels of CCR5 mRNA and protein expression were found in heterozygous versus wild-type homozygous MDMs and PBLs. Interestingly, wild-type homozygous MDMs showed higher levels of CCR5 mRNA expression compared with wild-type homozygous PBLs, while heterozygous MDMs had lower levels of CCR5 wild-type mRNA and a higher CCR5delta32/CCR5 mRNA ratio compared with heterozygous PBLs. These findings suggest that CCR5delta32 heterozygosity confers a different degree of protection against HIV-1 in PBLs and MDMs, depending on the ratio of wild-type and mutant CCR5 mRNA in the two cell types, and may delay virus spread in the host by preventing infection of monocytes and macrophages.
Ometto
L
L
Department of Oncology and Surgical Sciences, AIDS Reference Center, University of Padova, Padua, Italy.
Zanchetta
M
M
Cabrelle
A
A
Esposito
G
G
Mainardi
M
M
Chieco-Bianchi
L
L
De Rossi
A
A
D000328:Adult; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D017353:Gene Deletion; D015488:HIV Antigens; D016655:HIV Core Protein p24 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000821:virology; D008264:Macrophages / Q000821:virology*; D009000:Monocytes / Q000166:cytology; D016133:Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004279:DNA, Viral; D015488:HIV Antigens; D016655:HIV Core Protein p24; D019713:Receptors, CCR5