Strains of human immunodeficiency virus type 1 differ in their abilities to infect and replicate in primary human macrophages. Chimeric clones were constructed from a provirus unable to infect macrophages (NLHX) and envelope sequences (V3 loop) of viruses derived without cultivation from brain (YU2 and wl-lcl) or spleen (w2-1b4) tissues. The substituted V3 loop sequences in each case were sufficient to confer upon NLHX the ability to infect macrophages. Furthermore, an envelope domain immediately N terminal to the V3 loop also was found to modulate the level of replication in macrophages. These results demonstrate that an envelope determinant derived directly from patients with AIDS confers HIV-1 tropism for macrophages.
Nucleotide sequences for long terminal repeat (LTR), gag, the protease gene, and pol of a human T-lymphotropic virus type 1 (HTLV-1) isolate of probable Caribbean origin (HTLV-1CH) and a Zairian isolate (HTLV-1EL) were determined providing complete proviral sequences for these isolates. These sequences were compared with those available from previously analyzed isolates. Nucleotide sequence differences of 1.2-3.3% were identified among isolates for which complete genetic information was available. Nucleotide sequence diversity was distributed relatively evenly over the genome with 1.3-5.2% differences in the LTR, 1.1-2.9% differences in gag, 0.7-2.1% differences in the protease gene, 0.9-2.5% differences in pol, 0.9-2.4% differences in env, 0.0-1.4% differences in rex, and 0.1-2.6% differences in tax. There were 1.2-2.3% amino acid differences overall, with 0.8-1.6% nonconservative amino acid alterations. Nucleotide differences were not found in regions of the LTR which are important for transcriptional activity or Tax response. Within the Rex-response element, nucleotide differences were found predominantly in loop rather than stem structures, thus, maintaining the overall secondary structure necessary for Rex activity. Evolutionary tree analysis of the sequence differences suggests a predominant clustering of different HTLV1 strains according to geographical origin. An open reading frame was also identified on the minus DNA strand situated between the env and rex/tax genes which exhibits 0.1-6.9% nucleotide sequence variation among HTLV1 strains. The limited sequence variation among HTLV-1 strains is in striking contrast to the extensive heterogeneity seen among human immunodeficiency virus (HIV) strains.
The regulation of human immunodeficiency virus type 1 infection and replication in primary monocytes was investigated by mutagenesis of recombinant proviral clones containing an env determinant required for the infectivity of monocytes. Virus replication was assayed by determination of reverse transcriptase activity in culture fluids and by recovery of virus from monocytes following cocultivation with uninfected peripheral blood mononuclear cells. Three virus replication phenotypes were observed in monocytes: productive infection, silent infection, and no infection. Incorporation of the monocytetropic env determinant in a full-length clone incapable of infection or replication in primary monocytes (no infection) conferred the capacity for highly efficient virus replication in monocytes (productive infection). Clones with the env determinant but lacking either functional vpr or vpu genes generated lower replication levels in monocytes. Mutation of both vpr and vpu, however, resulted in nearly complete attenuation of virus replication in monocytes, despite subsequent virus recovery from infected monocytes by cocultivation with uninfected peripheral blood mononuclear cells (silent infection). These findings indicate a central role for the "accessory" genes vpu and vpr in productive human immunodeficiency virus type 1 replication in monocytes and indicate that vpu and vpr may be capable of functional complementation.
Human immunodeficiency virus type 1 isolates were obtained over a 3-year period from blood, brain, and lung of three patients in a clustered infectious outbreak. This included a blood donor who was initially asymptomatic but subsequently developed AIDS-related complex and two neonatal transfusion recipients who developed AIDS. Isolates from brain and lung replicated to >30-fold higher levels in primary monocyte cultures than did those from blood; no growth differences on primary lymphocytes were observed. Thirteen clones were obtained from seven isolates, and env sequences were determined. The predicted amino acid sequences among these clones differed by only 0.01% but differed by 15-27% when compared to previously sequenced iates from other
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